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8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 115
Oxide and hybrid nanostructures for therapeutic applications
Sudeshna Chandra KC Barick D Bahadur
Department of Metallurgical Engineering and Materials Science Indian Institute of Technology Bombay Mumbai 400076 India
a b s t r a c ta r t i c l e i n f o
Article history
Received 2 February 2011
Accepted 8 June 2011
Available online 15 June 2011
Keywords
Nanostructures
Hybrid
Stabilizers
Cancer therapy
The research on biomedical applications of nanoparticles has seen an upsurge in recent years due to their
unique capabilities in treatment of ailments Though there are ample reviews on the advances of
nanoparticles right from their fabrication to applications comparatively fewer reviews are available for the
nanostructured materials particularly on oxidesand hybrids These materials possess unique physicochemicalproperties with an ability to get functionalized at molecular and cellular level for biochemical interactions
Keeping the enormosity of the nanostructures in mind we intend to cover only the recent and most
noteworthy developments in this area We particularly emphasize on iron oxide and its derivatives zinc
oxides layered double hydroxides silica and binaryternary metal oxides and their applications in the area of
therapeutics This review also focuses on the designing of biodegradable and biocompatible nanocarriers and
critical issues related to their therapeutic applications Several representative examples discuss targeting
strategies and stimuli responsive nanocarriers and their therapeutics
copy 2011 Elsevier BV All rights reserved
Contents
1 Introduction 1267
2 Properties of the nanostructures to be used as carriers 1268
21 Size and shape 1268
22 Surface functionality 1268
3 Stabilization of oxide and hybrid nanostructures 1269
31 Organic stabilizers 1269
311 Small molecules 1269
312 Macromolecules 1269
32 Inorganic stabilizers 1270
33 Other stabilizers 1270
4 Therapeutic applications of oxide and hybrid nanostructures 1271
41 Challenges faced in the drug delivery 1271
411 Drug loading and release 1271
412 Cellular uptake and Imaging 1274
42 Hyperthermia treatment of cancer 1276
43 Other therapeutic applications 1277
44 Towards clinical trials 1277
5 Conclusion and future scope 1278Acknowledgements 1278
References 1278
1 Introduction
Advances in nanotechnology play an important role in designing
nanomaterials with speci1047297c functional properties that can address the
shortcomings in the area of diagnostics and therapeutics The
potential of nanomaterials has sparked enormous interest in the
Advanced Drug Delivery Reviews 63 (2011) 1267ndash1281
This review is part of the Advanced Drug Delivery Reviews theme issue on ldquoHybrid
Nanostructures for Diagnostics and Therapeuticsrdquo
Corresponding author
E-mail address dhirenbiitbacin (D Bahadur)
0169-409X$ ndash see front matter copy 2011 Elsevier BV All rights reserved
doi101016jaddr201106003
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
j o u r n a l h o m e p a g e w w w e l s ev i e r c o m l o c a t e a d d r
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 215
drug industry and has envisaged several applications as can be
evidenced by the exponential growth of activities in this 1047297eld The
advantages of the nanoparticles are mainly due to their nanoscale size
and large surface area with the ability to get functionalized with
targeting ligands therapeutic moieties and biomolecules [1] The fact
that the size of the nanoparticles is quite similar or smaller to the size
range of several bio entities makes them a natural companion in the
hybrid system Furthermore the nanoparticles can easily gain access
to various areas of the body without interfering into normal functionsand has the requisite potential for diagnostic and therapeutics The
ability to manipulatebind individual molecules at nanoscale has
provided ample opportunity for new therapeutic and diagnostic
applications [2] In this way either ldquohybridrdquo nanostructures can be
obtained or it may be embedded in biocompatible materials to impart
new functionalities Since multifunctional nanostructures are desir-
able for many applications like chemical and biological sensing and
diagnosis [3ndash8] sustained drug delivery [9] and hyperthermia [1011]
the fabrication of the nanostructures is signi1047297cant for controlling
crystalline morphology and surface architecture
Drug delivery is a key technology for the realization of nanome-
dicine and nanostructured mediated drug delivery systems play an
important role in improving the properties of already existing
therapeutic and diagnostic modalities Such systems with controlled
composition shape size and surface morphology are designed to
enhance solubility biocompatibility stability of the carrier and
cellular uptake The effectiveness of these has also been improved
signi1047297cantly as delivery vehicles with increased therapeutic payload
[3412] Ideally the nanostructured delivery vehicles should be able
to ef 1047297ciently load high weight fraction of drugs and must form a
stable suspension in an aqueous medium These also need to be
biodegradable andor biocompatible Drugs are usually encapsulated
in conjugated to or adsorbed onto surface of the nanocarrier and are
triggered released by heat pH or other modes of electromagnetic
radiation like ultrasound The nanoscale drug delivery system also
helps in stabilizing drug molecules [61314] which would otherwise
degrade rapidly and reduce drug ef 1047297cacy These bene1047297ts have
accounted for extensive research in the development of nanostruc-
tures and their interactions Most of these are hybrid nanomaterialsand are formed using lsquoweakrsquo molecular interactions such as H-
bonding van der Waal forces and other surface forces which require
low energy thereby allowing reversible and subsequent changes that
are essential for a bioprocess to take place Thus understanding the
interactions helps in broadening therapeutic strategies and designing
and improving drug delivery system In this context researchers have
studied the tunable properties of the nanomaterials by altering the
size shape and chemical composition and have developed strategies
to design biocompatible nanostructures of desired functionality with
and without biomolecules [15ndash21] Quantum dots (QDs) are an
archetype of this hybrid material which have gained interest due to
their tunable optical properties and have been considered as potential
optical probes for biological imaging They are resistant to degrada-
tion than other optical imaging probes and hence can track cellprocesses for longer periods and give more information on molecular
interactions drug delivery or locating a tumor and to arm it with toxic
therapies
Thus while this review aims to cover the fabrication and functiona-
lizationstabilization of various oxide and hybrid nanostructures it will
also attempt to discusstheir therapeutic applications We will emphasize
on magnetic nanostructuresfordrugdeliveryand magnetic hyperthermia
treatment of cancer After a brief introductionto thenanoparticulates and
the hybrids effective methods for functionalization and stabilization of
these structures are discussed The application of the oxides and hybrid
nanostructures in biomedicine is presented in the 1047297nal section In this
review noteworthy and most recent scienti1047297c advances dealing with the
therapeutic application of a wide variety of oxides and hybrid
nanostructures such as silica iron oxide and its derivatives zinc oxide
layereddouble hydroxides and binaryternary metal oxides arereported
We also emphasize here on designing of biodegradable biocompatible
thermosensitiveor pH sensitive nanocarriers fortheir usein drugdelivery
and hyperthermia Some recent advances with respect to sustained and
triggered drug release have been delineated Further the critical issues
relatedto thetherapeuticapplicationsof oxide andhybrid nanostructures
have been addressed and several representative examples to highlight
these applications have been covered brie1047298y in this review
2 Properties of the nanostructures to be used as carriers
The therapeutic applications of oxide and hybrid nanostructures
strongly depend on their physicochemical properties such as
permeability stability morphology (size shape and functionality)
and biocompatibility These physicochemical properties are dictated
by the types structures and orientations of the materials that
comprise the oxide and hybrid nanostructures The nanoparticles
and their hybrids used for therapeutic applications include both
porous and non-porous forms of non-toxic oxides having surface
functionality to which targeting ligands and additional imaging
modalities are anchored One of the most extensively investigated
oxide is iron oxide (γ-Fe2O3 Fe3O4) and its derivatives [22ndash26]
Therapeutic agents like drugs and biomolecules can then either be
physically embedded into the porous matrix or chemically bonded to
its surface Obvious advantages of using magnetic oxides in thera-
peutic applications include magnetic drug targeting heating ability
for hyperthemia and separation under external magnetic 1047297eld
21 Size and shape
The size and size distribution shape and surface functionality of
oxide nanocarriers are important parameters related to intracellular
uptake and biodistribution to a wider range of biological targets due
to their smaller size and relatively higher mobility The small sized
nanoparticles (b100 nm) have higher effective surface area facilitat-
ing easy attachment of ligands lower sedimentation rates (high
stability in colloidal suspension) and improved tissular diffusion For
most of therapeutic applications the 1047297rst signi1047297cant challenge is toavoid undesirable uptake of nanoparticles by the reticulo-endothelial
system (RES) The next step is to achieve selective targeting of the
system to the site of interest for the in-vivo studies In order to
overcome these problems nanoparticles should be small enough with
desired functionality to escape from the RES These nanoparticles
should remain in the circulation for prolonged time after injection
into bloodstream and should be capable of passing through the 1047297ne
capillary systems of organs and tissues avoiding vessel embolism
The size (hydrodynamic size) controls the nanoparticles concen-
tration pro1047297le in the blood vessel affects the mechanism of
nanoparticles clearance and mediates the permeability of nanoparti-
cles out of the vasculature [27] Small sized spherical nanoparticles
have higher diffusion rates which increase the concentration of
nanoparticles at the center of a blood vessel thereby limiting theinteractions of nanoparticles with endothelial cells and prolonging the
nanoparticles blood circulation time [28] Parket al [29] reported that
anisotropic iron oxide having high aspect ratio shows enhanced blood
circulation times over their spherical counterparts Other than size
and shape the pore size and its distribution have signi1047297cant effect on
the therapeutic applications due to its enhanced surface area and its
ability to contain and release drug [30] This aspect is discussed in a
later section
22 Surface functionality
The surface charge (zeta potential) of nanoparticles has an
important role to play in their physiological and aqueous colloidal
stability as well as in functionalization and designing promising
1268 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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nanostructures It can be easily controlled by the nature of the surface
groups in solution at a particular pH A high positive or negative zeta
potential value is an indication of the colloidal stability of nanopar-
ticles dueto theelectrostatic interaction It is reported that thesurface
of the nanoparticles determines their cellular interaction especially
during endocytosis and phagocytosis A strong correlation between
the surface charge and their cellular uptake ef 1047297ciency into different
cell lines has been observed It is further reported that the
hydrophobic groups on the surface of nanoparticles induce agglom-eration upon injection leading to rapid removal by the RES [31] Thus
surface modi1047297cation with hydrophilic molecules is essential to reduce
the opsonization potential through steric repulsion prolonging the
circulation time of nanoparticles The surface modi1047297cation of
nanoparticles for their aqueousphysiological stabilization is impor-
tant for most of the therapeutic applications and hence will be
discussed in more detail in the following section
3 Stabilization of oxide and hybrid nanostructures
Thecolloidal stabilization of the nanoparticles in both aqueous and
physiological medium is crucial for their therapeutic applications and
can be achieved by either charging the surface or conjugating it by
macromolecules for steric hindrance The surface charge can be
monitored and ensured by suitable means such as changing pH of the
medium or modifying with functional groups The steric stabilization
can be achieved by attachinggrafting of macromolecules such as
surfactant [32] or polymer [33] on the surface The steric stabilization
is indeedless sensitiveto the ionic strength of thesuspension medium
and can be easily achieved in both polar and non-polar medium The
oxide nanoparticles may be stabilized either during their synthesis or
in a post-synthesis process The in situ modi1047297cation during synthesis
process has several advantages including reduced agglomeration [34]
These biocompatible layers stabilize the nanoparticles and provides
accessible surface for routine conjugation of biomolecules
31 Organic stabilizers
311 Small moleculesThe small molecule targeting groups are predominantly attractive
forstabilizingoxide nanoparticles dueto their ease of preparation and
simple conjugation chemistry [35] The binding af 1047297nity of large
surfactant molecules or long polymer chains to the nanoparticles may
be lost due to steric hindrances which could otherwise be easily
overcome by using small molecules having multiple functional groups
such as carboxyl (COOH) amine (NH2) thiol (SH) phosphate and
sulfates These stabilizers can be tailored for dispersibility into
aqueous media or other biocompatible 1047298uids The presence of
hydroxyl groups on the surface of oxide nanoparticles provides a
versatile route for multiple functionalities Furthermore the presence
of large number of functional groups on the surface of nanoparticles
maybe used forlinkage of various biomolecules as well as drugsThus
the stability of the bonding between functional molecules andnanoparticles is crucial for therapeutic applications
Among various small molecules citrate moiety having multiple
carboxylate functionalities has been extensively used for the colloidal
stabilization of oxide nanoparticles The functional groups are
chemisorbed on the surface of the oxide nanoparticles by coordinat-
ing via one or two of the carboxylate functionalities depending upon
size and shape of the particles and leaving at least one carboxylic acid
group exposed to the solvent The free carboxylic groups render
suf 1047297cient negative charge on the surface of particles and hence make
them hydrophilic [36]
The short chain amines and aminosilanes are commonly used as
stabilizing agent in fabrication of various oxide nanoparticles
Recently Barick et al [2232] demonstrated a single-step facile
approach for highly water-stable assembly of amine-functionalized
Fe3O4 nanoparticles using thermal decomposition of Fe-chloride
precursors in ethylene glycol medium in the presence of sodium
acetate and ethylenediamine for bio-applications and compared their
magnetic resonance (MR)contrast behaviorIn addition to shortchain
amine and aminosilanes various amino acids [37] and peptides [38]
having multiple amine molecules have been used as stabilizer for
successful design of oxide nanoparticles
Small molecules having thiol functionality achieved great deal of
attention due to their higher binding af 1047297
nity towards metal and metaloxide nanoparticles The organosulfur compound 23-meso dimercap-
tosuccinic acid (DMSA) having two carboxylic and two thiol groups
have been commonly used as a stabilizing agent for inorganic oxides
MNPs have been stabilized with DMSA for tissue- and cell-targeted
delivery of therapeutic drugs in the lung [39] Speci1047297cally the
mechanism of the pro-in1047298ammatory effects of MNPsndashDMSA has been
investigated Maurizi et al [40] developed a convenient method to
stabilize free thiols onto the surface of iron oxide nanoparticles by post
functionalization using methoxy PEG 2000 silane and observed that
thiol functionalized nanoparticles were stable under physiological pH
Furthermore they have demonstrated that the stability of thiols can be
increased signi1047297cantly when DMSA is protected by polyethyleneglycol
(PEG) chains on the surface of nanoparticles DMSA stabilized aqueous
colloidal Fe3O4 nanoparticles were fabricated by introducing DMSA
molecules onto the surface of hydrophobic nanoparticles through
ligand exchange process [22]
312 Macromolecules
A variety of polymer molecules have been used for steric
stabilization of oxide nanoparticles in aqueous and high ionic strength
media [41ndash43] The polymer shell improves the stability of nanopar-
ticles in solution and allows the encapsulation of a therapeutic agent
Further these stabilizers provide a means to tailor the surface
properties of nanoparticles such as surface charge and chemical
functionality or their thermosensitive properties Major facts with
regard to polymeric stabilizer that may affect the performance of
nanocarriers include the chemical nature of the polymer (ie
hydrophilicityhydrophobicity biocompatibility and biodegradation)
the molecular weight of the polymer the manner in which thepolymer is grafted or attached (ie physically or chemically) the
conformation of the polymer and the degree of particle surface
coverage
Among various macromolecules dextran has been widely used for
surface modi1047297cation mostly because of its favorable size (chain
length) and biocompatibility which enables optimum polar in-
teractions (mainly chelation and hydrogen bonding) Dextran coating
not only provides a smooth outline and narrow size distribution but
also retains the essential superparamagnetic behavior of iron oxide
nanoparticles and a signi1047297cantly prolonged the storage stability [44]
Pradhan et al [45] fabricated dextran coated Fe3O4 nanoparticles by
co-precipitation method and compared their in vitro cytocompat-
ibility and cellular interactions with mouse 1047297broblast and human
cervical carcinoma cell lines with lauric acid-coated Fe3O4 nanopar-ticles The surface modi1047297cation was found to play an important role in
modulating biocompatibility and cellular interaction of MNPs
PEG is a hydrophilic water-soluble biocompatible polymer and
extensively used to increase blood circulation times Xie et al [42]
used controlled PEGylation method and dopamine as a cross-linker to
produce monodisperse Fe3O4 nanoparticles PEG was successfully
anchored on the nanoparticles through a covalent bond which
showed negligible aggregation in cell culture condition and reduced
non-speci1047297c uptake by macrophage cells These MNPs based systems
are capable of site-speci1047297c targeting and controlled drug release with
high biocompatibility The temperature-sensitive poly N-isopropyla-
crylamide (PNIPAAm) based MNPs are also of particular interest
because of their stimuli (temperature) responsiveness and enhanced
drug-loading ability[46]Wongetal [4748] fabricated thermoresponsive
1269S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
functionalized Fe3O4 nanoparticles [22] (b) dopamine-PEGfunctionalized Fe3O4 nanoparticles [42] (c) iridium-complex functionalized Fe3O4SiO2 coreshell nanoparticles [60] and
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 515
stabilized with different generation of polyamidoamine (PAMAM)
dendrimers for gene delivery [69] Chandra et al [70] demonstrated a
facile approach for the preparation of dendrimers coated Fe3O4
nanoparticles for drug delivery application In this method dendritic
structures were grown on the silane coated iron oxide nanoparticles
using methylacrylate and a biocompatible arginine as monomers
Taratula et al [71] reported a multifunctional superparamagnetic
nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)
for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes
to enhance serum stability and selective internalization by cancer cells
Bulte andcoworkers labeled human neuralstem cells andmesenchymal
stem cells with magnetodendrimers through a non-speci1047297c membrane
adsorption process with subsequent intracellular localization in endo-
somes The labeled neural stem-cells derived oligodendroglial pro-
genitors were readily detected in vivo by MR signals The magnetomers
were also used to track the olfactory ensheathing glia grafted into rat
spinal cord in vivo [72] However there were no speci1047297c interaction
between the particles and the target cells since the magnetodendrimers
did not have any speci1047297c surface modi1047297cation Modi1047297cation of the
magnetodendrimers with biological receptors or antibodies opens up
the possibility of their use for speci1047297c application right from targeting to
a site transiting the cell membrane and making intracellular delivery
4 Therapeutic applications of oxide and hybrid nanostructures
Controlled synthesis of individual monodisperse nanoparticles led to
the evolution of nanostructures with improved magnetic conducting
1047298uorescent and targeting properties for potential bio-medical applica-
tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-
sites encompassing a broad range of materials and variousnanostructural
morphologies (spherical cylindrical star-likeetc) are becoming themain
building blocks for next generation of drug delivery systems
41 Challenges faced in the drug delivery
Most of the delivery systems have limitations of poor pharmaco-
kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other
parts of organsand tissues In addition many of these systems need to
provide stability a sustained or burst release non toxicity solubility
in aqueous media and bio-distribution to suit a particular therapy
These therapeutic agents could be in the form of microcapsules
dispersion adsorbed entities as a conjugate to nanoparticulates or
loaded to porous or hollow structures Let us look at some of the
potential drug delivery systems which include several oxide systems
as well as hybrid structures Although many organic systems such as
liposomes dendrimers or other macromolecules are used as excellent
drug carriers but we are limiting our discussion only to inorganic
oxidehydroxide systems or their hybrids with organic moieties In
this context a number of organicinorganic hybrids have been
investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been
approved by FDA for clinical use of these most are based on non-
targeted delivery system The miniaturization of the materials to
nanoscale incorporates new properties within themselves which
should be carefully characterized to avoid any un-intended side
effects The increased activity of the nanostructures can either be
desirable in terms of therapeutic capacity cell barrier penetration for
drug delivery induction of oxidativestress or cellular dysfunction or a
combine effect of both [74]
The toxicity of the nanoparticles remains a major issue towards
fabrication of nanomedicine and it mainly depends on factors like
chemical composition surface chemistry dose quanti1047297cation particle
size biodistribution and biodegradability etc Fe particles with a
uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the
technical requirementsfor clinical use including high biocompatibility
in living cells injection through blood vessels without any clotting
high absorption rate for magnetic hyperthermia and as contrast agent
in MRI [75] The in-vivo animal experiments showed that a total iron
dose about 06 mgkg showed no apparent acute toxicity or side
effects over a monitoring period of 3 weeks Biocompatibility results
of PVA coated magnetic nanoparticles on L929 and K562 cells
demonstrated acceptable cell viability levels following exposure of
upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2
magnetoliposomes (HML) for effective targeting of breast cancer cells
and cytocidal abilities of the HML has been achieved using cell culture
models Their studies show that the growth of tumor is almost
suppressed by just two hyperthermia treatments and no iron
accumulation was observed in the organs (eg liver spleen brain
heart etc) of the HML-injected mice Further in a rat model also no
speci1047297c pathologic changes were observed in liver spleen heart and
brain even after repeated subcutaneous injection of HML A signi1047297cant
decrease in glioblastoma cell survival was observed after treatment
withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron
oxide nanoparticles Furtheran increase in animal survivalwas found after
convection-enhanced delivery (CED) of magnetic nanoparticles in mice
implanted with tumorigenic glioblastoma xenografts [78] There has to be
focus on developing targeted controlled and sustained drug release
systems which can convey drugs more effectively increase patient
compliancereduce cytotoxicityto normal cells andextend circulationtime
411 Drug loading and release
The ef 1047297ciency of drug loading and release strongly depends upon
the ability to design a biocompatible colloidal nanocarrier that allows
high loading of drug moleculeswithout any premature release of drug
before reaching the destination Thus the carrier should have good
biocompatibility properties with higher encapsulation ef 1047297ciency and
should exhibit site speci1047297c control release of drug molecules
Among a variety of drug carriers mesoporous silica and zinc oxide
nanoparticles have several striking features for use in the drug
delivery These nanoparticles have large surface area and porous
interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to
preferentially store various drug molecules of interest while the size
and shape of the nanoparticles can be tailored to maximize the
cellular uptake [79] Mesoporous silica has been successfully used for
storing of drug molecules (Ibuprofen) into the pores through
hydrogen bond interaction between the ibuprofen and the silanol
groups present in the pore wall [80] It was observed that the release
rate of ibuprofen in a simulated body 1047298uid solution increased
signi1047297cantly under the pulsed pressure drop An interesting photo-
thermal modulated drug delivery system was designed based on
silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded
by a gold shell [81] The peak extinctions of the nanoshells are easily
tuned over a wide range of wavelengths particularly in the near
infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to
absorption Also irradiation of SiO2ndashAu nanoshells at their peak
extinction coef 1047297cient results in the conversion of light to heat energy
that produces a local rise in temperature Further SiO2ndashAu nanoshells
were embedded into a temperature-sensitive hydrogels (N-isopro-
pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of
initiating a temperature changewith light fortriggered release of drug
molecules The composite hydrogels had the extinction spectrum of
the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in
response to temperature (50 degC) and laser irradiation
Recently the drug-loading ef 1047297ciency of a highly mesoporous
spherical three dimensional ZnO nanoassemblies was investigated
using doxorubicin hydrochloride (DOX) as a model drug by our
research group [82] The interaction and entrapment of drug molecules
1271S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
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The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1115
oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
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[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
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[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
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[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
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[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
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[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
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[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
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[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
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[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
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[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
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[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
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J Pharma 365 (2009) 180ndash189
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
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[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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drug industry and has envisaged several applications as can be
evidenced by the exponential growth of activities in this 1047297eld The
advantages of the nanoparticles are mainly due to their nanoscale size
and large surface area with the ability to get functionalized with
targeting ligands therapeutic moieties and biomolecules [1] The fact
that the size of the nanoparticles is quite similar or smaller to the size
range of several bio entities makes them a natural companion in the
hybrid system Furthermore the nanoparticles can easily gain access
to various areas of the body without interfering into normal functionsand has the requisite potential for diagnostic and therapeutics The
ability to manipulatebind individual molecules at nanoscale has
provided ample opportunity for new therapeutic and diagnostic
applications [2] In this way either ldquohybridrdquo nanostructures can be
obtained or it may be embedded in biocompatible materials to impart
new functionalities Since multifunctional nanostructures are desir-
able for many applications like chemical and biological sensing and
diagnosis [3ndash8] sustained drug delivery [9] and hyperthermia [1011]
the fabrication of the nanostructures is signi1047297cant for controlling
crystalline morphology and surface architecture
Drug delivery is a key technology for the realization of nanome-
dicine and nanostructured mediated drug delivery systems play an
important role in improving the properties of already existing
therapeutic and diagnostic modalities Such systems with controlled
composition shape size and surface morphology are designed to
enhance solubility biocompatibility stability of the carrier and
cellular uptake The effectiveness of these has also been improved
signi1047297cantly as delivery vehicles with increased therapeutic payload
[3412] Ideally the nanostructured delivery vehicles should be able
to ef 1047297ciently load high weight fraction of drugs and must form a
stable suspension in an aqueous medium These also need to be
biodegradable andor biocompatible Drugs are usually encapsulated
in conjugated to or adsorbed onto surface of the nanocarrier and are
triggered released by heat pH or other modes of electromagnetic
radiation like ultrasound The nanoscale drug delivery system also
helps in stabilizing drug molecules [61314] which would otherwise
degrade rapidly and reduce drug ef 1047297cacy These bene1047297ts have
accounted for extensive research in the development of nanostruc-
tures and their interactions Most of these are hybrid nanomaterialsand are formed using lsquoweakrsquo molecular interactions such as H-
bonding van der Waal forces and other surface forces which require
low energy thereby allowing reversible and subsequent changes that
are essential for a bioprocess to take place Thus understanding the
interactions helps in broadening therapeutic strategies and designing
and improving drug delivery system In this context researchers have
studied the tunable properties of the nanomaterials by altering the
size shape and chemical composition and have developed strategies
to design biocompatible nanostructures of desired functionality with
and without biomolecules [15ndash21] Quantum dots (QDs) are an
archetype of this hybrid material which have gained interest due to
their tunable optical properties and have been considered as potential
optical probes for biological imaging They are resistant to degrada-
tion than other optical imaging probes and hence can track cellprocesses for longer periods and give more information on molecular
interactions drug delivery or locating a tumor and to arm it with toxic
therapies
Thus while this review aims to cover the fabrication and functiona-
lizationstabilization of various oxide and hybrid nanostructures it will
also attempt to discusstheir therapeutic applications We will emphasize
on magnetic nanostructuresfordrugdeliveryand magnetic hyperthermia
treatment of cancer After a brief introductionto thenanoparticulates and
the hybrids effective methods for functionalization and stabilization of
these structures are discussed The application of the oxides and hybrid
nanostructures in biomedicine is presented in the 1047297nal section In this
review noteworthy and most recent scienti1047297c advances dealing with the
therapeutic application of a wide variety of oxides and hybrid
nanostructures such as silica iron oxide and its derivatives zinc oxide
layereddouble hydroxides and binaryternary metal oxides arereported
We also emphasize here on designing of biodegradable biocompatible
thermosensitiveor pH sensitive nanocarriers fortheir usein drugdelivery
and hyperthermia Some recent advances with respect to sustained and
triggered drug release have been delineated Further the critical issues
relatedto thetherapeuticapplicationsof oxide andhybrid nanostructures
have been addressed and several representative examples to highlight
these applications have been covered brie1047298y in this review
2 Properties of the nanostructures to be used as carriers
The therapeutic applications of oxide and hybrid nanostructures
strongly depend on their physicochemical properties such as
permeability stability morphology (size shape and functionality)
and biocompatibility These physicochemical properties are dictated
by the types structures and orientations of the materials that
comprise the oxide and hybrid nanostructures The nanoparticles
and their hybrids used for therapeutic applications include both
porous and non-porous forms of non-toxic oxides having surface
functionality to which targeting ligands and additional imaging
modalities are anchored One of the most extensively investigated
oxide is iron oxide (γ-Fe2O3 Fe3O4) and its derivatives [22ndash26]
Therapeutic agents like drugs and biomolecules can then either be
physically embedded into the porous matrix or chemically bonded to
its surface Obvious advantages of using magnetic oxides in thera-
peutic applications include magnetic drug targeting heating ability
for hyperthemia and separation under external magnetic 1047297eld
21 Size and shape
The size and size distribution shape and surface functionality of
oxide nanocarriers are important parameters related to intracellular
uptake and biodistribution to a wider range of biological targets due
to their smaller size and relatively higher mobility The small sized
nanoparticles (b100 nm) have higher effective surface area facilitat-
ing easy attachment of ligands lower sedimentation rates (high
stability in colloidal suspension) and improved tissular diffusion For
most of therapeutic applications the 1047297rst signi1047297cant challenge is toavoid undesirable uptake of nanoparticles by the reticulo-endothelial
system (RES) The next step is to achieve selective targeting of the
system to the site of interest for the in-vivo studies In order to
overcome these problems nanoparticles should be small enough with
desired functionality to escape from the RES These nanoparticles
should remain in the circulation for prolonged time after injection
into bloodstream and should be capable of passing through the 1047297ne
capillary systems of organs and tissues avoiding vessel embolism
The size (hydrodynamic size) controls the nanoparticles concen-
tration pro1047297le in the blood vessel affects the mechanism of
nanoparticles clearance and mediates the permeability of nanoparti-
cles out of the vasculature [27] Small sized spherical nanoparticles
have higher diffusion rates which increase the concentration of
nanoparticles at the center of a blood vessel thereby limiting theinteractions of nanoparticles with endothelial cells and prolonging the
nanoparticles blood circulation time [28] Parket al [29] reported that
anisotropic iron oxide having high aspect ratio shows enhanced blood
circulation times over their spherical counterparts Other than size
and shape the pore size and its distribution have signi1047297cant effect on
the therapeutic applications due to its enhanced surface area and its
ability to contain and release drug [30] This aspect is discussed in a
later section
22 Surface functionality
The surface charge (zeta potential) of nanoparticles has an
important role to play in their physiological and aqueous colloidal
stability as well as in functionalization and designing promising
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nanostructures It can be easily controlled by the nature of the surface
groups in solution at a particular pH A high positive or negative zeta
potential value is an indication of the colloidal stability of nanopar-
ticles dueto theelectrostatic interaction It is reported that thesurface
of the nanoparticles determines their cellular interaction especially
during endocytosis and phagocytosis A strong correlation between
the surface charge and their cellular uptake ef 1047297ciency into different
cell lines has been observed It is further reported that the
hydrophobic groups on the surface of nanoparticles induce agglom-eration upon injection leading to rapid removal by the RES [31] Thus
surface modi1047297cation with hydrophilic molecules is essential to reduce
the opsonization potential through steric repulsion prolonging the
circulation time of nanoparticles The surface modi1047297cation of
nanoparticles for their aqueousphysiological stabilization is impor-
tant for most of the therapeutic applications and hence will be
discussed in more detail in the following section
3 Stabilization of oxide and hybrid nanostructures
Thecolloidal stabilization of the nanoparticles in both aqueous and
physiological medium is crucial for their therapeutic applications and
can be achieved by either charging the surface or conjugating it by
macromolecules for steric hindrance The surface charge can be
monitored and ensured by suitable means such as changing pH of the
medium or modifying with functional groups The steric stabilization
can be achieved by attachinggrafting of macromolecules such as
surfactant [32] or polymer [33] on the surface The steric stabilization
is indeedless sensitiveto the ionic strength of thesuspension medium
and can be easily achieved in both polar and non-polar medium The
oxide nanoparticles may be stabilized either during their synthesis or
in a post-synthesis process The in situ modi1047297cation during synthesis
process has several advantages including reduced agglomeration [34]
These biocompatible layers stabilize the nanoparticles and provides
accessible surface for routine conjugation of biomolecules
31 Organic stabilizers
311 Small moleculesThe small molecule targeting groups are predominantly attractive
forstabilizingoxide nanoparticles dueto their ease of preparation and
simple conjugation chemistry [35] The binding af 1047297nity of large
surfactant molecules or long polymer chains to the nanoparticles may
be lost due to steric hindrances which could otherwise be easily
overcome by using small molecules having multiple functional groups
such as carboxyl (COOH) amine (NH2) thiol (SH) phosphate and
sulfates These stabilizers can be tailored for dispersibility into
aqueous media or other biocompatible 1047298uids The presence of
hydroxyl groups on the surface of oxide nanoparticles provides a
versatile route for multiple functionalities Furthermore the presence
of large number of functional groups on the surface of nanoparticles
maybe used forlinkage of various biomolecules as well as drugsThus
the stability of the bonding between functional molecules andnanoparticles is crucial for therapeutic applications
Among various small molecules citrate moiety having multiple
carboxylate functionalities has been extensively used for the colloidal
stabilization of oxide nanoparticles The functional groups are
chemisorbed on the surface of the oxide nanoparticles by coordinat-
ing via one or two of the carboxylate functionalities depending upon
size and shape of the particles and leaving at least one carboxylic acid
group exposed to the solvent The free carboxylic groups render
suf 1047297cient negative charge on the surface of particles and hence make
them hydrophilic [36]
The short chain amines and aminosilanes are commonly used as
stabilizing agent in fabrication of various oxide nanoparticles
Recently Barick et al [2232] demonstrated a single-step facile
approach for highly water-stable assembly of amine-functionalized
Fe3O4 nanoparticles using thermal decomposition of Fe-chloride
precursors in ethylene glycol medium in the presence of sodium
acetate and ethylenediamine for bio-applications and compared their
magnetic resonance (MR)contrast behaviorIn addition to shortchain
amine and aminosilanes various amino acids [37] and peptides [38]
having multiple amine molecules have been used as stabilizer for
successful design of oxide nanoparticles
Small molecules having thiol functionality achieved great deal of
attention due to their higher binding af 1047297
nity towards metal and metaloxide nanoparticles The organosulfur compound 23-meso dimercap-
tosuccinic acid (DMSA) having two carboxylic and two thiol groups
have been commonly used as a stabilizing agent for inorganic oxides
MNPs have been stabilized with DMSA for tissue- and cell-targeted
delivery of therapeutic drugs in the lung [39] Speci1047297cally the
mechanism of the pro-in1047298ammatory effects of MNPsndashDMSA has been
investigated Maurizi et al [40] developed a convenient method to
stabilize free thiols onto the surface of iron oxide nanoparticles by post
functionalization using methoxy PEG 2000 silane and observed that
thiol functionalized nanoparticles were stable under physiological pH
Furthermore they have demonstrated that the stability of thiols can be
increased signi1047297cantly when DMSA is protected by polyethyleneglycol
(PEG) chains on the surface of nanoparticles DMSA stabilized aqueous
colloidal Fe3O4 nanoparticles were fabricated by introducing DMSA
molecules onto the surface of hydrophobic nanoparticles through
ligand exchange process [22]
312 Macromolecules
A variety of polymer molecules have been used for steric
stabilization of oxide nanoparticles in aqueous and high ionic strength
media [41ndash43] The polymer shell improves the stability of nanopar-
ticles in solution and allows the encapsulation of a therapeutic agent
Further these stabilizers provide a means to tailor the surface
properties of nanoparticles such as surface charge and chemical
functionality or their thermosensitive properties Major facts with
regard to polymeric stabilizer that may affect the performance of
nanocarriers include the chemical nature of the polymer (ie
hydrophilicityhydrophobicity biocompatibility and biodegradation)
the molecular weight of the polymer the manner in which thepolymer is grafted or attached (ie physically or chemically) the
conformation of the polymer and the degree of particle surface
coverage
Among various macromolecules dextran has been widely used for
surface modi1047297cation mostly because of its favorable size (chain
length) and biocompatibility which enables optimum polar in-
teractions (mainly chelation and hydrogen bonding) Dextran coating
not only provides a smooth outline and narrow size distribution but
also retains the essential superparamagnetic behavior of iron oxide
nanoparticles and a signi1047297cantly prolonged the storage stability [44]
Pradhan et al [45] fabricated dextran coated Fe3O4 nanoparticles by
co-precipitation method and compared their in vitro cytocompat-
ibility and cellular interactions with mouse 1047297broblast and human
cervical carcinoma cell lines with lauric acid-coated Fe3O4 nanopar-ticles The surface modi1047297cation was found to play an important role in
modulating biocompatibility and cellular interaction of MNPs
PEG is a hydrophilic water-soluble biocompatible polymer and
extensively used to increase blood circulation times Xie et al [42]
used controlled PEGylation method and dopamine as a cross-linker to
produce monodisperse Fe3O4 nanoparticles PEG was successfully
anchored on the nanoparticles through a covalent bond which
showed negligible aggregation in cell culture condition and reduced
non-speci1047297c uptake by macrophage cells These MNPs based systems
are capable of site-speci1047297c targeting and controlled drug release with
high biocompatibility The temperature-sensitive poly N-isopropyla-
crylamide (PNIPAAm) based MNPs are also of particular interest
because of their stimuli (temperature) responsiveness and enhanced
drug-loading ability[46]Wongetal [4748] fabricated thermoresponsive
1269S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
functionalized Fe3O4 nanoparticles [22] (b) dopamine-PEGfunctionalized Fe3O4 nanoparticles [42] (c) iridium-complex functionalized Fe3O4SiO2 coreshell nanoparticles [60] and
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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stabilized with different generation of polyamidoamine (PAMAM)
dendrimers for gene delivery [69] Chandra et al [70] demonstrated a
facile approach for the preparation of dendrimers coated Fe3O4
nanoparticles for drug delivery application In this method dendritic
structures were grown on the silane coated iron oxide nanoparticles
using methylacrylate and a biocompatible arginine as monomers
Taratula et al [71] reported a multifunctional superparamagnetic
nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)
for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes
to enhance serum stability and selective internalization by cancer cells
Bulte andcoworkers labeled human neuralstem cells andmesenchymal
stem cells with magnetodendrimers through a non-speci1047297c membrane
adsorption process with subsequent intracellular localization in endo-
somes The labeled neural stem-cells derived oligodendroglial pro-
genitors were readily detected in vivo by MR signals The magnetomers
were also used to track the olfactory ensheathing glia grafted into rat
spinal cord in vivo [72] However there were no speci1047297c interaction
between the particles and the target cells since the magnetodendrimers
did not have any speci1047297c surface modi1047297cation Modi1047297cation of the
magnetodendrimers with biological receptors or antibodies opens up
the possibility of their use for speci1047297c application right from targeting to
a site transiting the cell membrane and making intracellular delivery
4 Therapeutic applications of oxide and hybrid nanostructures
Controlled synthesis of individual monodisperse nanoparticles led to
the evolution of nanostructures with improved magnetic conducting
1047298uorescent and targeting properties for potential bio-medical applica-
tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-
sites encompassing a broad range of materials and variousnanostructural
morphologies (spherical cylindrical star-likeetc) are becoming themain
building blocks for next generation of drug delivery systems
41 Challenges faced in the drug delivery
Most of the delivery systems have limitations of poor pharmaco-
kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other
parts of organsand tissues In addition many of these systems need to
provide stability a sustained or burst release non toxicity solubility
in aqueous media and bio-distribution to suit a particular therapy
These therapeutic agents could be in the form of microcapsules
dispersion adsorbed entities as a conjugate to nanoparticulates or
loaded to porous or hollow structures Let us look at some of the
potential drug delivery systems which include several oxide systems
as well as hybrid structures Although many organic systems such as
liposomes dendrimers or other macromolecules are used as excellent
drug carriers but we are limiting our discussion only to inorganic
oxidehydroxide systems or their hybrids with organic moieties In
this context a number of organicinorganic hybrids have been
investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been
approved by FDA for clinical use of these most are based on non-
targeted delivery system The miniaturization of the materials to
nanoscale incorporates new properties within themselves which
should be carefully characterized to avoid any un-intended side
effects The increased activity of the nanostructures can either be
desirable in terms of therapeutic capacity cell barrier penetration for
drug delivery induction of oxidativestress or cellular dysfunction or a
combine effect of both [74]
The toxicity of the nanoparticles remains a major issue towards
fabrication of nanomedicine and it mainly depends on factors like
chemical composition surface chemistry dose quanti1047297cation particle
size biodistribution and biodegradability etc Fe particles with a
uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the
technical requirementsfor clinical use including high biocompatibility
in living cells injection through blood vessels without any clotting
high absorption rate for magnetic hyperthermia and as contrast agent
in MRI [75] The in-vivo animal experiments showed that a total iron
dose about 06 mgkg showed no apparent acute toxicity or side
effects over a monitoring period of 3 weeks Biocompatibility results
of PVA coated magnetic nanoparticles on L929 and K562 cells
demonstrated acceptable cell viability levels following exposure of
upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2
magnetoliposomes (HML) for effective targeting of breast cancer cells
and cytocidal abilities of the HML has been achieved using cell culture
models Their studies show that the growth of tumor is almost
suppressed by just two hyperthermia treatments and no iron
accumulation was observed in the organs (eg liver spleen brain
heart etc) of the HML-injected mice Further in a rat model also no
speci1047297c pathologic changes were observed in liver spleen heart and
brain even after repeated subcutaneous injection of HML A signi1047297cant
decrease in glioblastoma cell survival was observed after treatment
withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron
oxide nanoparticles Furtheran increase in animal survivalwas found after
convection-enhanced delivery (CED) of magnetic nanoparticles in mice
implanted with tumorigenic glioblastoma xenografts [78] There has to be
focus on developing targeted controlled and sustained drug release
systems which can convey drugs more effectively increase patient
compliancereduce cytotoxicityto normal cells andextend circulationtime
411 Drug loading and release
The ef 1047297ciency of drug loading and release strongly depends upon
the ability to design a biocompatible colloidal nanocarrier that allows
high loading of drug moleculeswithout any premature release of drug
before reaching the destination Thus the carrier should have good
biocompatibility properties with higher encapsulation ef 1047297ciency and
should exhibit site speci1047297c control release of drug molecules
Among a variety of drug carriers mesoporous silica and zinc oxide
nanoparticles have several striking features for use in the drug
delivery These nanoparticles have large surface area and porous
interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to
preferentially store various drug molecules of interest while the size
and shape of the nanoparticles can be tailored to maximize the
cellular uptake [79] Mesoporous silica has been successfully used for
storing of drug molecules (Ibuprofen) into the pores through
hydrogen bond interaction between the ibuprofen and the silanol
groups present in the pore wall [80] It was observed that the release
rate of ibuprofen in a simulated body 1047298uid solution increased
signi1047297cantly under the pulsed pressure drop An interesting photo-
thermal modulated drug delivery system was designed based on
silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded
by a gold shell [81] The peak extinctions of the nanoshells are easily
tuned over a wide range of wavelengths particularly in the near
infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to
absorption Also irradiation of SiO2ndashAu nanoshells at their peak
extinction coef 1047297cient results in the conversion of light to heat energy
that produces a local rise in temperature Further SiO2ndashAu nanoshells
were embedded into a temperature-sensitive hydrogels (N-isopro-
pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of
initiating a temperature changewith light fortriggered release of drug
molecules The composite hydrogels had the extinction spectrum of
the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in
response to temperature (50 degC) and laser irradiation
Recently the drug-loading ef 1047297ciency of a highly mesoporous
spherical three dimensional ZnO nanoassemblies was investigated
using doxorubicin hydrochloride (DOX) as a model drug by our
research group [82] The interaction and entrapment of drug molecules
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with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
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The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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nanostructures It can be easily controlled by the nature of the surface
groups in solution at a particular pH A high positive or negative zeta
potential value is an indication of the colloidal stability of nanopar-
ticles dueto theelectrostatic interaction It is reported that thesurface
of the nanoparticles determines their cellular interaction especially
during endocytosis and phagocytosis A strong correlation between
the surface charge and their cellular uptake ef 1047297ciency into different
cell lines has been observed It is further reported that the
hydrophobic groups on the surface of nanoparticles induce agglom-eration upon injection leading to rapid removal by the RES [31] Thus
surface modi1047297cation with hydrophilic molecules is essential to reduce
the opsonization potential through steric repulsion prolonging the
circulation time of nanoparticles The surface modi1047297cation of
nanoparticles for their aqueousphysiological stabilization is impor-
tant for most of the therapeutic applications and hence will be
discussed in more detail in the following section
3 Stabilization of oxide and hybrid nanostructures
Thecolloidal stabilization of the nanoparticles in both aqueous and
physiological medium is crucial for their therapeutic applications and
can be achieved by either charging the surface or conjugating it by
macromolecules for steric hindrance The surface charge can be
monitored and ensured by suitable means such as changing pH of the
medium or modifying with functional groups The steric stabilization
can be achieved by attachinggrafting of macromolecules such as
surfactant [32] or polymer [33] on the surface The steric stabilization
is indeedless sensitiveto the ionic strength of thesuspension medium
and can be easily achieved in both polar and non-polar medium The
oxide nanoparticles may be stabilized either during their synthesis or
in a post-synthesis process The in situ modi1047297cation during synthesis
process has several advantages including reduced agglomeration [34]
These biocompatible layers stabilize the nanoparticles and provides
accessible surface for routine conjugation of biomolecules
31 Organic stabilizers
311 Small moleculesThe small molecule targeting groups are predominantly attractive
forstabilizingoxide nanoparticles dueto their ease of preparation and
simple conjugation chemistry [35] The binding af 1047297nity of large
surfactant molecules or long polymer chains to the nanoparticles may
be lost due to steric hindrances which could otherwise be easily
overcome by using small molecules having multiple functional groups
such as carboxyl (COOH) amine (NH2) thiol (SH) phosphate and
sulfates These stabilizers can be tailored for dispersibility into
aqueous media or other biocompatible 1047298uids The presence of
hydroxyl groups on the surface of oxide nanoparticles provides a
versatile route for multiple functionalities Furthermore the presence
of large number of functional groups on the surface of nanoparticles
maybe used forlinkage of various biomolecules as well as drugsThus
the stability of the bonding between functional molecules andnanoparticles is crucial for therapeutic applications
Among various small molecules citrate moiety having multiple
carboxylate functionalities has been extensively used for the colloidal
stabilization of oxide nanoparticles The functional groups are
chemisorbed on the surface of the oxide nanoparticles by coordinat-
ing via one or two of the carboxylate functionalities depending upon
size and shape of the particles and leaving at least one carboxylic acid
group exposed to the solvent The free carboxylic groups render
suf 1047297cient negative charge on the surface of particles and hence make
them hydrophilic [36]
The short chain amines and aminosilanes are commonly used as
stabilizing agent in fabrication of various oxide nanoparticles
Recently Barick et al [2232] demonstrated a single-step facile
approach for highly water-stable assembly of amine-functionalized
Fe3O4 nanoparticles using thermal decomposition of Fe-chloride
precursors in ethylene glycol medium in the presence of sodium
acetate and ethylenediamine for bio-applications and compared their
magnetic resonance (MR)contrast behaviorIn addition to shortchain
amine and aminosilanes various amino acids [37] and peptides [38]
having multiple amine molecules have been used as stabilizer for
successful design of oxide nanoparticles
Small molecules having thiol functionality achieved great deal of
attention due to their higher binding af 1047297
nity towards metal and metaloxide nanoparticles The organosulfur compound 23-meso dimercap-
tosuccinic acid (DMSA) having two carboxylic and two thiol groups
have been commonly used as a stabilizing agent for inorganic oxides
MNPs have been stabilized with DMSA for tissue- and cell-targeted
delivery of therapeutic drugs in the lung [39] Speci1047297cally the
mechanism of the pro-in1047298ammatory effects of MNPsndashDMSA has been
investigated Maurizi et al [40] developed a convenient method to
stabilize free thiols onto the surface of iron oxide nanoparticles by post
functionalization using methoxy PEG 2000 silane and observed that
thiol functionalized nanoparticles were stable under physiological pH
Furthermore they have demonstrated that the stability of thiols can be
increased signi1047297cantly when DMSA is protected by polyethyleneglycol
(PEG) chains on the surface of nanoparticles DMSA stabilized aqueous
colloidal Fe3O4 nanoparticles were fabricated by introducing DMSA
molecules onto the surface of hydrophobic nanoparticles through
ligand exchange process [22]
312 Macromolecules
A variety of polymer molecules have been used for steric
stabilization of oxide nanoparticles in aqueous and high ionic strength
media [41ndash43] The polymer shell improves the stability of nanopar-
ticles in solution and allows the encapsulation of a therapeutic agent
Further these stabilizers provide a means to tailor the surface
properties of nanoparticles such as surface charge and chemical
functionality or their thermosensitive properties Major facts with
regard to polymeric stabilizer that may affect the performance of
nanocarriers include the chemical nature of the polymer (ie
hydrophilicityhydrophobicity biocompatibility and biodegradation)
the molecular weight of the polymer the manner in which thepolymer is grafted or attached (ie physically or chemically) the
conformation of the polymer and the degree of particle surface
coverage
Among various macromolecules dextran has been widely used for
surface modi1047297cation mostly because of its favorable size (chain
length) and biocompatibility which enables optimum polar in-
teractions (mainly chelation and hydrogen bonding) Dextran coating
not only provides a smooth outline and narrow size distribution but
also retains the essential superparamagnetic behavior of iron oxide
nanoparticles and a signi1047297cantly prolonged the storage stability [44]
Pradhan et al [45] fabricated dextran coated Fe3O4 nanoparticles by
co-precipitation method and compared their in vitro cytocompat-
ibility and cellular interactions with mouse 1047297broblast and human
cervical carcinoma cell lines with lauric acid-coated Fe3O4 nanopar-ticles The surface modi1047297cation was found to play an important role in
modulating biocompatibility and cellular interaction of MNPs
PEG is a hydrophilic water-soluble biocompatible polymer and
extensively used to increase blood circulation times Xie et al [42]
used controlled PEGylation method and dopamine as a cross-linker to
produce monodisperse Fe3O4 nanoparticles PEG was successfully
anchored on the nanoparticles through a covalent bond which
showed negligible aggregation in cell culture condition and reduced
non-speci1047297c uptake by macrophage cells These MNPs based systems
are capable of site-speci1047297c targeting and controlled drug release with
high biocompatibility The temperature-sensitive poly N-isopropyla-
crylamide (PNIPAAm) based MNPs are also of particular interest
because of their stimuli (temperature) responsiveness and enhanced
drug-loading ability[46]Wongetal [4748] fabricated thermoresponsive
1269S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
functionalized Fe3O4 nanoparticles [22] (b) dopamine-PEGfunctionalized Fe3O4 nanoparticles [42] (c) iridium-complex functionalized Fe3O4SiO2 coreshell nanoparticles [60] and
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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stabilized with different generation of polyamidoamine (PAMAM)
dendrimers for gene delivery [69] Chandra et al [70] demonstrated a
facile approach for the preparation of dendrimers coated Fe3O4
nanoparticles for drug delivery application In this method dendritic
structures were grown on the silane coated iron oxide nanoparticles
using methylacrylate and a biocompatible arginine as monomers
Taratula et al [71] reported a multifunctional superparamagnetic
nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)
for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes
to enhance serum stability and selective internalization by cancer cells
Bulte andcoworkers labeled human neuralstem cells andmesenchymal
stem cells with magnetodendrimers through a non-speci1047297c membrane
adsorption process with subsequent intracellular localization in endo-
somes The labeled neural stem-cells derived oligodendroglial pro-
genitors were readily detected in vivo by MR signals The magnetomers
were also used to track the olfactory ensheathing glia grafted into rat
spinal cord in vivo [72] However there were no speci1047297c interaction
between the particles and the target cells since the magnetodendrimers
did not have any speci1047297c surface modi1047297cation Modi1047297cation of the
magnetodendrimers with biological receptors or antibodies opens up
the possibility of their use for speci1047297c application right from targeting to
a site transiting the cell membrane and making intracellular delivery
4 Therapeutic applications of oxide and hybrid nanostructures
Controlled synthesis of individual monodisperse nanoparticles led to
the evolution of nanostructures with improved magnetic conducting
1047298uorescent and targeting properties for potential bio-medical applica-
tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-
sites encompassing a broad range of materials and variousnanostructural
morphologies (spherical cylindrical star-likeetc) are becoming themain
building blocks for next generation of drug delivery systems
41 Challenges faced in the drug delivery
Most of the delivery systems have limitations of poor pharmaco-
kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other
parts of organsand tissues In addition many of these systems need to
provide stability a sustained or burst release non toxicity solubility
in aqueous media and bio-distribution to suit a particular therapy
These therapeutic agents could be in the form of microcapsules
dispersion adsorbed entities as a conjugate to nanoparticulates or
loaded to porous or hollow structures Let us look at some of the
potential drug delivery systems which include several oxide systems
as well as hybrid structures Although many organic systems such as
liposomes dendrimers or other macromolecules are used as excellent
drug carriers but we are limiting our discussion only to inorganic
oxidehydroxide systems or their hybrids with organic moieties In
this context a number of organicinorganic hybrids have been
investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been
approved by FDA for clinical use of these most are based on non-
targeted delivery system The miniaturization of the materials to
nanoscale incorporates new properties within themselves which
should be carefully characterized to avoid any un-intended side
effects The increased activity of the nanostructures can either be
desirable in terms of therapeutic capacity cell barrier penetration for
drug delivery induction of oxidativestress or cellular dysfunction or a
combine effect of both [74]
The toxicity of the nanoparticles remains a major issue towards
fabrication of nanomedicine and it mainly depends on factors like
chemical composition surface chemistry dose quanti1047297cation particle
size biodistribution and biodegradability etc Fe particles with a
uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the
technical requirementsfor clinical use including high biocompatibility
in living cells injection through blood vessels without any clotting
high absorption rate for magnetic hyperthermia and as contrast agent
in MRI [75] The in-vivo animal experiments showed that a total iron
dose about 06 mgkg showed no apparent acute toxicity or side
effects over a monitoring period of 3 weeks Biocompatibility results
of PVA coated magnetic nanoparticles on L929 and K562 cells
demonstrated acceptable cell viability levels following exposure of
upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2
magnetoliposomes (HML) for effective targeting of breast cancer cells
and cytocidal abilities of the HML has been achieved using cell culture
models Their studies show that the growth of tumor is almost
suppressed by just two hyperthermia treatments and no iron
accumulation was observed in the organs (eg liver spleen brain
heart etc) of the HML-injected mice Further in a rat model also no
speci1047297c pathologic changes were observed in liver spleen heart and
brain even after repeated subcutaneous injection of HML A signi1047297cant
decrease in glioblastoma cell survival was observed after treatment
withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron
oxide nanoparticles Furtheran increase in animal survivalwas found after
convection-enhanced delivery (CED) of magnetic nanoparticles in mice
implanted with tumorigenic glioblastoma xenografts [78] There has to be
focus on developing targeted controlled and sustained drug release
systems which can convey drugs more effectively increase patient
compliancereduce cytotoxicityto normal cells andextend circulationtime
411 Drug loading and release
The ef 1047297ciency of drug loading and release strongly depends upon
the ability to design a biocompatible colloidal nanocarrier that allows
high loading of drug moleculeswithout any premature release of drug
before reaching the destination Thus the carrier should have good
biocompatibility properties with higher encapsulation ef 1047297ciency and
should exhibit site speci1047297c control release of drug molecules
Among a variety of drug carriers mesoporous silica and zinc oxide
nanoparticles have several striking features for use in the drug
delivery These nanoparticles have large surface area and porous
interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to
preferentially store various drug molecules of interest while the size
and shape of the nanoparticles can be tailored to maximize the
cellular uptake [79] Mesoporous silica has been successfully used for
storing of drug molecules (Ibuprofen) into the pores through
hydrogen bond interaction between the ibuprofen and the silanol
groups present in the pore wall [80] It was observed that the release
rate of ibuprofen in a simulated body 1047298uid solution increased
signi1047297cantly under the pulsed pressure drop An interesting photo-
thermal modulated drug delivery system was designed based on
silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded
by a gold shell [81] The peak extinctions of the nanoshells are easily
tuned over a wide range of wavelengths particularly in the near
infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to
absorption Also irradiation of SiO2ndashAu nanoshells at their peak
extinction coef 1047297cient results in the conversion of light to heat energy
that produces a local rise in temperature Further SiO2ndashAu nanoshells
were embedded into a temperature-sensitive hydrogels (N-isopro-
pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of
initiating a temperature changewith light fortriggered release of drug
molecules The composite hydrogels had the extinction spectrum of
the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in
response to temperature (50 degC) and laser irradiation
Recently the drug-loading ef 1047297ciency of a highly mesoporous
spherical three dimensional ZnO nanoassemblies was investigated
using doxorubicin hydrochloride (DOX) as a model drug by our
research group [82] The interaction and entrapment of drug molecules
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with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
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The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
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[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
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[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
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[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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PNIPAAm microgel through LBL technique possessing both thermore-
sponsivity and magnetism withhigh speci1047297c absorption ratewhich could
open up new prospects for remotely controlled drug carriers Other
polymers that display some thermosensitivity near physiological or
hyperthermic conditions include hydroxypropyl cellulose (HPC) [49]
pluronic triblock copolymer surfactants and block copolymers [50] The
formulationof thenanoparticulatescanalso be realized by using Foodand
Drug Administration (FDA) approved biodegradable polymers such as
poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) andvarious novel biodegradable copolymers such as poly(lactic acid-co-
ethylene glycol) (PLEA) and copolymer of (lactic acid-D-α-tocopherol
polyethylene glycol 1000 succinate) (PLA-TPGS) [5152] Various other
polymers used for aqueous stabilization of iron oxide magnetic
nanoparticles are sodium alginate [53] L -arginine [54] polyacrylic acid
(PAA) [55] poly(allylamine) [56] acrypol 934 [26] and chitosan [57]
32 Inorganic stabilizers
Silica (SiO2) gold (Au) and silver (Ag) are extensively used for
surface modi1047297cation of the oxide nanoparticles which forms corendash
shell structures and provides stability to the nanoparticles in solution
and further help in binding various biological molecules and drugs to
the surface of nanoparticles through suitable functional groups The
stabilization of oxide nanoparticles by silica can easily be achieved
either by Stoumlber process or microemulsion method [5859] SiO2
stabilized Fe3O4 corendashshell nanoparticles functionalized with phos-
phorescent iridium-complex has been used for applications in
photodynamic therapy [60] Surface modi1047297cation with alumina of a
substituted garnet system in an attempt to tune the TC of the
magnetic oxides for in vivo control during hyperthermia is also
noteworthy [61]
There has been considerable interest in stabilizing oxide nano-
particles with noble metal shells such as Au and Ag The magnetic
oxide nanoparticles with metal coating can be effectively stabilized in
corrosive biological conditions and can be readily functionalized
through the well-established metal-sulfur chemistry The magnetic
corendashshell nanoparticles with tunable plasmonic properties have
great potential for nanoparticle-based diagnostic and therapeuticapplications [62ndash64] Dumbbell shaped AundashFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as
target-speci1047297c nanocarriers to deliver cisplatin into Her2-positive
breast cancer cells with strong therapeutic effects When compared to
conventional single-component iron oxide NPs the AundashFe3O4 NPs
were advantageous in facilitating stepwise attachment of an antibody
to a platin complex and also for serving as magnetic and optical probe
for tracking the drug in the cells [64] The most signi1047297cant advantage
of this composite system is that it provides controlled magneto-
optical properties long term stability to the magnetic core andfunctionality to the nanoparticles
33 Other stabilizers
The amphiphilic molecules such as liposomes and micelles have
been successfully used to stabilize oxide nanoparticles for therapeutic
applications [6566] Liposomes have also the ability to encapsulate a
large number of nanoparticles and deliver them together to the speci1047297c
target site Both hydrophilic and hydrophobic foreign molecules such as
drugs and biomolecules can be easily anchored to the amphiphilic
liposomes and micelles which can enhance the multifunctionality of a
system Martina et al [67] developed magnetic 1047298uid-loaded liposomes
by encapsulating γ-Fe2O3 nanocrystals within unilamellar vesicles of
egg phosphatidylcholine and DSPE-PEG2000 Further it was also found
that phospholipid molecules (egg phosphatidylcholine) which are
essential precursors for liposome formation may also in1047298uence the
nucleation and growth characteristics of MNPs The effects of phospha-
tidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and
their properties have been well discussed [68] Fig 1 shows a schematic
representation of TEM micrographs of various stabilizers used for
stabilizing magnetic nanoparticles
Recently dendrimers a novel class of macromolecules with highly
ordered structure hasreceived signi1047297cantattention for functionalization
and stabilization of oxide nanoparticles Dendrimer coating alters the
surface charge functionality and reactivity and enhances the stability
and dispersibility of the nanoparticles Furthermore the presence of
multiple functional groups with symmetric perfection and nanometer
scale internal cavities enables dendritic stabilized nanoparticles for
incredible biomedical applications including targeting imaging andsensing Magnetic iron oxide nanoparticles have been successfully
Fig 1 Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs (a) 23-dimercaptosuccinic acid (DMSA)
functionalized Fe3O4 nanoparticles [22] (b) dopamine-PEGfunctionalized Fe3O4 nanoparticles [42] (c) iridium-complex functionalized Fe3O4SiO2 coreshell nanoparticles [60] and
(d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65] (Reproduced with permission from [22] copyright RSC publications [4260] Copyright John
Wiley and Sons Inc and [65] Copyright 2006 American Chemical Society Publications)
1270 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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stabilized with different generation of polyamidoamine (PAMAM)
dendrimers for gene delivery [69] Chandra et al [70] demonstrated a
facile approach for the preparation of dendrimers coated Fe3O4
nanoparticles for drug delivery application In this method dendritic
structures were grown on the silane coated iron oxide nanoparticles
using methylacrylate and a biocompatible arginine as monomers
Taratula et al [71] reported a multifunctional superparamagnetic
nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)
for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes
to enhance serum stability and selective internalization by cancer cells
Bulte andcoworkers labeled human neuralstem cells andmesenchymal
stem cells with magnetodendrimers through a non-speci1047297c membrane
adsorption process with subsequent intracellular localization in endo-
somes The labeled neural stem-cells derived oligodendroglial pro-
genitors were readily detected in vivo by MR signals The magnetomers
were also used to track the olfactory ensheathing glia grafted into rat
spinal cord in vivo [72] However there were no speci1047297c interaction
between the particles and the target cells since the magnetodendrimers
did not have any speci1047297c surface modi1047297cation Modi1047297cation of the
magnetodendrimers with biological receptors or antibodies opens up
the possibility of their use for speci1047297c application right from targeting to
a site transiting the cell membrane and making intracellular delivery
4 Therapeutic applications of oxide and hybrid nanostructures
Controlled synthesis of individual monodisperse nanoparticles led to
the evolution of nanostructures with improved magnetic conducting
1047298uorescent and targeting properties for potential bio-medical applica-
tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-
sites encompassing a broad range of materials and variousnanostructural
morphologies (spherical cylindrical star-likeetc) are becoming themain
building blocks for next generation of drug delivery systems
41 Challenges faced in the drug delivery
Most of the delivery systems have limitations of poor pharmaco-
kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other
parts of organsand tissues In addition many of these systems need to
provide stability a sustained or burst release non toxicity solubility
in aqueous media and bio-distribution to suit a particular therapy
These therapeutic agents could be in the form of microcapsules
dispersion adsorbed entities as a conjugate to nanoparticulates or
loaded to porous or hollow structures Let us look at some of the
potential drug delivery systems which include several oxide systems
as well as hybrid structures Although many organic systems such as
liposomes dendrimers or other macromolecules are used as excellent
drug carriers but we are limiting our discussion only to inorganic
oxidehydroxide systems or their hybrids with organic moieties In
this context a number of organicinorganic hybrids have been
investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been
approved by FDA for clinical use of these most are based on non-
targeted delivery system The miniaturization of the materials to
nanoscale incorporates new properties within themselves which
should be carefully characterized to avoid any un-intended side
effects The increased activity of the nanostructures can either be
desirable in terms of therapeutic capacity cell barrier penetration for
drug delivery induction of oxidativestress or cellular dysfunction or a
combine effect of both [74]
The toxicity of the nanoparticles remains a major issue towards
fabrication of nanomedicine and it mainly depends on factors like
chemical composition surface chemistry dose quanti1047297cation particle
size biodistribution and biodegradability etc Fe particles with a
uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the
technical requirementsfor clinical use including high biocompatibility
in living cells injection through blood vessels without any clotting
high absorption rate for magnetic hyperthermia and as contrast agent
in MRI [75] The in-vivo animal experiments showed that a total iron
dose about 06 mgkg showed no apparent acute toxicity or side
effects over a monitoring period of 3 weeks Biocompatibility results
of PVA coated magnetic nanoparticles on L929 and K562 cells
demonstrated acceptable cell viability levels following exposure of
upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2
magnetoliposomes (HML) for effective targeting of breast cancer cells
and cytocidal abilities of the HML has been achieved using cell culture
models Their studies show that the growth of tumor is almost
suppressed by just two hyperthermia treatments and no iron
accumulation was observed in the organs (eg liver spleen brain
heart etc) of the HML-injected mice Further in a rat model also no
speci1047297c pathologic changes were observed in liver spleen heart and
brain even after repeated subcutaneous injection of HML A signi1047297cant
decrease in glioblastoma cell survival was observed after treatment
withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron
oxide nanoparticles Furtheran increase in animal survivalwas found after
convection-enhanced delivery (CED) of magnetic nanoparticles in mice
implanted with tumorigenic glioblastoma xenografts [78] There has to be
focus on developing targeted controlled and sustained drug release
systems which can convey drugs more effectively increase patient
compliancereduce cytotoxicityto normal cells andextend circulationtime
411 Drug loading and release
The ef 1047297ciency of drug loading and release strongly depends upon
the ability to design a biocompatible colloidal nanocarrier that allows
high loading of drug moleculeswithout any premature release of drug
before reaching the destination Thus the carrier should have good
biocompatibility properties with higher encapsulation ef 1047297ciency and
should exhibit site speci1047297c control release of drug molecules
Among a variety of drug carriers mesoporous silica and zinc oxide
nanoparticles have several striking features for use in the drug
delivery These nanoparticles have large surface area and porous
interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to
preferentially store various drug molecules of interest while the size
and shape of the nanoparticles can be tailored to maximize the
cellular uptake [79] Mesoporous silica has been successfully used for
storing of drug molecules (Ibuprofen) into the pores through
hydrogen bond interaction between the ibuprofen and the silanol
groups present in the pore wall [80] It was observed that the release
rate of ibuprofen in a simulated body 1047298uid solution increased
signi1047297cantly under the pulsed pressure drop An interesting photo-
thermal modulated drug delivery system was designed based on
silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded
by a gold shell [81] The peak extinctions of the nanoshells are easily
tuned over a wide range of wavelengths particularly in the near
infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to
absorption Also irradiation of SiO2ndashAu nanoshells at their peak
extinction coef 1047297cient results in the conversion of light to heat energy
that produces a local rise in temperature Further SiO2ndashAu nanoshells
were embedded into a temperature-sensitive hydrogels (N-isopro-
pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of
initiating a temperature changewith light fortriggered release of drug
molecules The composite hydrogels had the extinction spectrum of
the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in
response to temperature (50 degC) and laser irradiation
Recently the drug-loading ef 1047297ciency of a highly mesoporous
spherical three dimensional ZnO nanoassemblies was investigated
using doxorubicin hydrochloride (DOX) as a model drug by our
research group [82] The interaction and entrapment of drug molecules
1271S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
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thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
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[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
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[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
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[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
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[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
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[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
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stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
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[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
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httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
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[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
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discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
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[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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stabilized with different generation of polyamidoamine (PAMAM)
dendrimers for gene delivery [69] Chandra et al [70] demonstrated a
facile approach for the preparation of dendrimers coated Fe3O4
nanoparticles for drug delivery application In this method dendritic
structures were grown on the silane coated iron oxide nanoparticles
using methylacrylate and a biocompatible arginine as monomers
Taratula et al [71] reported a multifunctional superparamagnetic
nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5)
for siRNA delivery system for cancer therapy PEG coating and LHRHtargeting peptide was incorporated into SPIO-PPI G5ndashsiRNA complexes
to enhance serum stability and selective internalization by cancer cells
Bulte andcoworkers labeled human neuralstem cells andmesenchymal
stem cells with magnetodendrimers through a non-speci1047297c membrane
adsorption process with subsequent intracellular localization in endo-
somes The labeled neural stem-cells derived oligodendroglial pro-
genitors were readily detected in vivo by MR signals The magnetomers
were also used to track the olfactory ensheathing glia grafted into rat
spinal cord in vivo [72] However there were no speci1047297c interaction
between the particles and the target cells since the magnetodendrimers
did not have any speci1047297c surface modi1047297cation Modi1047297cation of the
magnetodendrimers with biological receptors or antibodies opens up
the possibility of their use for speci1047297c application right from targeting to
a site transiting the cell membrane and making intracellular delivery
4 Therapeutic applications of oxide and hybrid nanostructures
Controlled synthesis of individual monodisperse nanoparticles led to
the evolution of nanostructures with improved magnetic conducting
1047298uorescent and targeting properties for potential bio-medical applica-
tions Corendashshell nanoparticles LBL assembly [73] and other nanocompo-
sites encompassing a broad range of materials and variousnanostructural
morphologies (spherical cylindrical star-likeetc) are becoming themain
building blocks for next generation of drug delivery systems
41 Challenges faced in the drug delivery
Most of the delivery systems have limitations of poor pharmaco-
kinetics and targeting ef 1047297ciency It is important that the drugmolecule is carried only to the affected site without affecting other
parts of organsand tissues In addition many of these systems need to
provide stability a sustained or burst release non toxicity solubility
in aqueous media and bio-distribution to suit a particular therapy
These therapeutic agents could be in the form of microcapsules
dispersion adsorbed entities as a conjugate to nanoparticulates or
loaded to porous or hollow structures Let us look at some of the
potential drug delivery systems which include several oxide systems
as well as hybrid structures Although many organic systems such as
liposomes dendrimers or other macromolecules are used as excellent
drug carriers but we are limiting our discussion only to inorganic
oxidehydroxide systems or their hybrids with organic moieties In
this context a number of organicinorganic hybrids have been
investigated as delivery vehicles to develop effective therapeuticmodalities So far only a few therapeutic products have been
approved by FDA for clinical use of these most are based on non-
targeted delivery system The miniaturization of the materials to
nanoscale incorporates new properties within themselves which
should be carefully characterized to avoid any un-intended side
effects The increased activity of the nanostructures can either be
desirable in terms of therapeutic capacity cell barrier penetration for
drug delivery induction of oxidativestress or cellular dysfunction or a
combine effect of both [74]
The toxicity of the nanoparticles remains a major issue towards
fabrication of nanomedicine and it mainly depends on factors like
chemical composition surface chemistry dose quanti1047297cation particle
size biodistribution and biodegradability etc Fe particles with a
uniform epitaxial shell of MgO and the nanoparticles satis1047297ed all the
technical requirementsfor clinical use including high biocompatibility
in living cells injection through blood vessels without any clotting
high absorption rate for magnetic hyperthermia and as contrast agent
in MRI [75] The in-vivo animal experiments showed that a total iron
dose about 06 mgkg showed no apparent acute toxicity or side
effects over a monitoring period of 3 weeks Biocompatibility results
of PVA coated magnetic nanoparticles on L929 and K562 cells
demonstrated acceptable cell viability levels following exposure of
upto 20 mM iron concentration and neither apoptosis nor necrosistook place [76] Kikumori and co-workers [77] developed anti-HER2
magnetoliposomes (HML) for effective targeting of breast cancer cells
and cytocidal abilities of the HML has been achieved using cell culture
models Their studies show that the growth of tumor is almost
suppressed by just two hyperthermia treatments and no iron
accumulation was observed in the organs (eg liver spleen brain
heart etc) of the HML-injected mice Further in a rat model also no
speci1047297c pathologic changes were observed in liver spleen heart and
brain even after repeated subcutaneous injection of HML A signi1047297cant
decrease in glioblastoma cell survival was observed after treatment
withepidermalgrowth factorreceptor(EGFRvIII)antibody-conjugated iron
oxide nanoparticles Furtheran increase in animal survivalwas found after
convection-enhanced delivery (CED) of magnetic nanoparticles in mice
implanted with tumorigenic glioblastoma xenografts [78] There has to be
focus on developing targeted controlled and sustained drug release
systems which can convey drugs more effectively increase patient
compliancereduce cytotoxicityto normal cells andextend circulationtime
411 Drug loading and release
The ef 1047297ciency of drug loading and release strongly depends upon
the ability to design a biocompatible colloidal nanocarrier that allows
high loading of drug moleculeswithout any premature release of drug
before reaching the destination Thus the carrier should have good
biocompatibility properties with higher encapsulation ef 1047297ciency and
should exhibit site speci1047297c control release of drug molecules
Among a variety of drug carriers mesoporous silica and zinc oxide
nanoparticles have several striking features for use in the drug
delivery These nanoparticles have large surface area and porous
interiorsthat can be used as reservoirs for storing drug molecules Thepore size and surrounding environment can be easily tuned to
preferentially store various drug molecules of interest while the size
and shape of the nanoparticles can be tailored to maximize the
cellular uptake [79] Mesoporous silica has been successfully used for
storing of drug molecules (Ibuprofen) into the pores through
hydrogen bond interaction between the ibuprofen and the silanol
groups present in the pore wall [80] It was observed that the release
rate of ibuprofen in a simulated body 1047298uid solution increased
signi1047297cantly under the pulsed pressure drop An interesting photo-
thermal modulated drug delivery system was designed based on
silicandashgold (SiO2ndashAu) nanoshells consisting of a silica core surrounded
by a gold shell [81] The peak extinctions of the nanoshells are easily
tuned over a wide range of wavelengths particularly in the near
infrared (IR) region of the spectrum and the light in this region istransmitted through tissue with relatively little attenuation due to
absorption Also irradiation of SiO2ndashAu nanoshells at their peak
extinction coef 1047297cient results in the conversion of light to heat energy
that produces a local rise in temperature Further SiO2ndashAu nanoshells
were embedded into a temperature-sensitive hydrogels (N-isopro-
pylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of
initiating a temperature changewith light fortriggered release of drug
molecules The composite hydrogels had the extinction spectrum of
the SiO2ndashAu nanoshells in which the hydrogels collapsed reversibly in
response to temperature (50 degC) and laser irradiation
Recently the drug-loading ef 1047297ciency of a highly mesoporous
spherical three dimensional ZnO nanoassemblies was investigated
using doxorubicin hydrochloride (DOX) as a model drug by our
research group [82] The interaction and entrapment of drug molecules
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with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
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The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 615
with ZnO were evident from the quenching of the 1047298uorescence as well
as the shift in band positions The drug release showed strong
dependence on the pH of the medium ultrasound energy (continuous
or pulsatile) andthe natureof encapsulents(Fig2a b)The drug-loaded
ZnOnanoassembliesreleasedabout90 and65 of loadeddrug in acetatebuffer-pH 4 and acetate buffer-pH 5 media respectively after 33 h
About 26DOX wasreleasedfrom theDOX-loaded ZnOnanoassemblies
under continuous irradiation of ultrasoundfor 60 minin aqueous media
whereas in pulsatile mode (ONndashOFF condition) about 425 of loaded
drug was released
Another approach which received great attention is of combining
anti-cancer drug therapy with quantum dot technology Yuan et al
[83] synthesized blue-light emitting ZnO quantum dots (QDs) and
then combined them with biodegradable chitosan (N-acetylglucosa-
mine) to use in tumor-targeted drug delivery The hydrophilicity and
cationic surface charge of chitosan enhanced the stability of the QDs
Drug-loading ef 1047297ciency of these carriers was about ~75 with an
initial rapid drug release followed by a controlled release This study
has thrown new insight towards the application of water-dispersedZnO QDs (2ndash4 nm) in designing of new drug release carrier with long-
term 1047298uorescence stability
Recently Li et al [84] studied the cytotoxicity and photodynamic
effect of different-sized ZnO nanoparticles to cancer cells They have
observed that ZnO nanoparticles exerted time and dose dependent
cytotoxicity for cancer cells The suppression ability of ZnO nanopar-
ticles for cancer cells proliferation was found to be enhanced by UV
irradiation These results suggested that ZnO nanoparticles could play
an important role in drug delivery to enhance the accumulation and
the synergistic cytotoxicity of daunorubicin in the target SMMC-7721
cells Thus the 1047298uorescent ZnO nanoparticles could be developed for
simultaneous detection and localization of multiple solid cancer
biomarkers enabling the personalization of therapeutic regimens for
each patient These nanoparticles can be easily conjugated with
tumor-speci1047297c ligands and used for tumor-selective delivery of
chemotherapeutic agents as well as photodynamic cancer therapy
The slight solubilization of the biocompatible ZnO nanocarriers at
lower pH can also facilitates the drug release Such pH-triggered
release is advantageous in chemotherapy since the relatively lowerpH in tumors speci1047297cally stimulate the drug release at the target site
In addition these systems also work under the ultrasound or UV
irradiation (continuous or pulsatile) for controlled and targeted
on-demand drug delivery
Targeting is the biggest challenge Generally when the drug is
administered it would not have any site of preference and hence may
distribute all over the organs which in many cases are undesirable due
to its toxic nature Active targeting is a preferred modality through the
modi1047297cation of nanoparticles with ligands which has the attributes to
enhance the therapeutic ef 1047297cacy and reduce the side effects relative to
conventional therapeutics Various factors such as delivery vehicles
drugs and diseases in1047298uence the targeted delivery It is therefore
desired that the delivery system has some moieties attached to the
carrier which either gets bound to the diseased site or preferentiallyoverexpress to the target site Ligand mediated cellular uptake is a
valuable pathway for therapeutics Some of the important targeting
ligands are folate antibodies and their fragments and different
peptides For diseases like tumor or in1047298ation passive targeting also
occurs due to leaky vasculature Most tumors exhibit pores within their
vasculature of typical size between 350and 400 nmThis facilitates drug
concentration in tumor or in1047298ated regions by extravasation Any
targeting however demands that nanocarriers circulate in blood for
extended times Nanoparticulates otherwise exhibit short circulation
half lives which can be enhanced by suitable surface modi1047297cation with
long circulating molecules like PEG Due to its several favorable
properties like hydrophilic nature low degree of immunogenicity and
availability of terminal primary hydroxyl groups for functionalization
PEG is most extensively used for this purpose
Fig 2 Triggered drug release in presence of various external stimuli such as (a) pH [82] (b) ultrasound [82] (c) temperature [66] and (d) AC magnetic 1047297eld [70] (Reproduced with
permission from [8270] copyright RSC publications and [66] copyright Elsevier License)
1272 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 715
The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
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thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 715
The magnetically targeted-drug delivery system is considered one
of the most popular and ef 1047297cient methods In this technique the drug
carrying MNPs with a suitable carrier system taken orally or injected
through vein may be directed to the diseased area by an external
magnetic1047297eld A novel method forentrapping positively charged drug
molecules (DOX) onto the surface of negatively charged citrate-
stabilized 8ndash10 nm Fe3O4 magnetic nanoparticles (CA-MNP) through
electrostatic interactions is recently developed by Nigam et al [85]
The drug loading ef 1047297
ciency of about 90 (ww) was achieved byelectrostatic interaction of DOX with CA-MNP and the DOX conju-
gated CA-MNP exhibited a sustained release pro1047297le It has been
observed that bound drug molecules are released in appreciable
amounts in the mild acidic environments of the tumor Storage and
release of cisplatin using porous hollow nanoparticles (PHNPs) of
Fe3O4 were studied [86] The porous shell (pore size of about 2ndash4 nm)
was stable in neutral or basic physiological conditions and cisplatin
releases from the cavity through a diffusion-controlled slow process
A compositemembranebased on thermosensitive poly(NIPAAm)-
based nanogels and magnetite nanoparticles was developed which
enabled rapid and tunable drug delivery upon the application of an
external oscillating magnetic 1047297eld [87] Onndashoff release of sodium
1047298uorescein over multiple magnetic cycles has been successfully
demonstrated using prototype non-cytotoxic biocompatible mem-
brane-based switching devices The total drug dose delivered was
directly proportional to the duration of the ldquoonrdquo pulse Corendashshell
nanoparticles of similar composition showed signi1047297cantly lower
systemic toxicity and DOX encapsulation ef 1047297ciency of 72 [88] The
drug release study indicated that the polymer is sensitive to
temperature which undergoes phase change at LCST resulting into
the collapse of nanoparticles thereby releasing more drugs After 72 h
78 of the encapsulated DOX was released at 41 degC whereas at 4 degC
and 37 degC ~26 and ~43 was released respectively Released drugs
were also active in destroying prostate cancer cells and the
nanoparticle uptake by these cells was dependent on dose and
incubation time Folate-targeted doxorubicin-containing magnetic
liposomes (MagFolDox) shows temperature dependent drug release
(Fig 2c) after 1 h incubation in PBS and FBS medium [66] In 50 FBS
upto 46 DOX was released from FolDox but in the presence of magnetic 1047297eld it increased to 52 Zhang et al [89] described in vitro
drug delivery response of polyethylene glycol (PEG)-functionalized
magnetite (Fe3O4) nanoparticles which were activated with a folic
acid andconjugated with doxorubicin Here the drug release involved
Fickian diffusion through pores in thepolymer matrix Thediffusion of
drug from biodegradable polymer is often dictated by the excluded
volume and hydrodynamic interactions Other factors that in1047298uenced
the drug release response are drug solubility polymer degradation
and polymerndashdrug interaction
The composites of biocompatible bovine serum albumin (BSA)ndash
dextranndashchitosan nanoparticles were effectively used to load DOX into
the nanoparticles after changing the pH of their composite to 74 [90]
These nanoparticles exhibited faster release of doxorubicin at pH 50
(acetate buffer) than at pH 74 (PBS buffer) Theprotonated doxorubicindecreases the hydrophobic interactions which lead to electrostatic
repulsion between the nanoparticles and the doxorubicin thereby
releasing at a faster rate The performance of gelatin coated iron oxide
MNPs as drug carrier was evaluated for drug targeting of doxorubicin
(DOX) [91] where thedrug loading wasdone using adsorptionas well as
desolvationcross-linking techniques Compared to adsorption tech-
nique desolvationcross-linking technique improved the ef 1047297ciency of
drug loading regardless the type of gelatin used for the coating The
DOX-loaded particles showed pH responsive drug release leading to
accelerated release of drug at pH 4 compared to pH 74
Recently dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug
delivery application in presence and absence of AC magnetic 1047297eld are
explored by Chandra et al [70] The pH triggered release pro1047297le ofDOX
loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54 Interestingly thesteadylinear release steepens
upon application of the AC magnetic 1047297eld About 35 of the drug was
released in the 1047297rst 45 min in the absence of a magnetic 1047297eld whereas
the release percentage further increased to 80 under the continuous
application of AC magnetic 1047297eld over the next 15 min The enhanced
release of the drug molecules in the AC magnetic 1047297eld is favorable for
combined therapy involving drug delivery and hyperthermia (Fig 2d)
Furthermore the surface of dendritic magnetic nanocarriers can be
easily tailored to provide precise anchoring sites to conjugate variousbiomolecules Due to their versatility the dendritic magnetic nanocar-
riers can also incorporate both hydrophilic and hydrophobic drugs
Based on the various studies one may conclude that functional
nanoparticles coupled with biological targeting agents and drug
moleculesis promising as drug delivery vehicles withenhanced imaging
and therapeutic ef 1047297cacy However there are many factors which affect
the ef 1047297cacy of a developed system For example the presence of target
and drug molecules on the nanoparticles may interfere with the
targeting capability and cellular uptake of the nanoparticles Further
coupling of different chemical functionalities on a surface of nanopar-
ticles often leads to a low yield synthetic process This can be overcome
by using multicomponent nanohybrid systems wherein target mole-
cules imaging probe and a drug can be anchored on different surface
functionality on the samesystem [8366] Another concern in theuse of
hybrid nanostructures of different sizes and shapes is their movement
through the systemic circulation as they are intended to experience
various 1047298uid environments and might behave differently due to the
effect of viscous force Agglomeration of the nanosystems cannot be
ruled out as they move through the narrow capillaries which might lead
to clogging of blood vessels [92] Further the nanohybrid systems may
have restricted or indiscriminate movement across the biological
barriers which dictates their behavior and fate upon introduction into
the body (biodistribution) Functionalization of the nanoparticles with
various macromolecules biopolymers or dendrimers enables the
nanoparticles to interact with the biological environment and protect
them from degradation [93] As our knowledge of various multi-
functional and hybrid nanostructures grow the enormity of the
Fig 3 Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells
incubatedat (a)37 degCand (b)4 degCfor 30 min[96] andoptical imagesof KB cells treated
by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation
[100] (Reproduced with permission from [96] copyright Springer and [100] copyright
American Chemical Society Publications)
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
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thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
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[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
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[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
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[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
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[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
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nanoparticles Conjugation and release of doxorubicin for therapeutic
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
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[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
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[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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challenges become obvious Thus while designing the hybrid nanos-
tructures one must have to take care of certain features that are
essential for effective intracellular targeting These include (i) clearance
from the circulation (ii) withheld release of drug at non-targeted sites
(iii) delivery of drugndashnanocarrier and release of drug at targeted site
(iv) removal of drugfrom the target site and (v) effective elimination of
the nanocarrier from the body
412 Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on
the internalization of the nanoparticles within the cells Thus the
ef 1047297ciencywith which cellscan be loaded with nanoparticles is a major
determinant for imaging sensitivity at the single cell level Some cells
such as macrophages can be readily labeled with adequate quantities
of nanoparticles due to their inherent ability to phagocytose material
in the extracellular medium however there are many other cell lines
including cancer cells which do not readily phagocytose This
challenge can be overcome by direct conjugation of cell-penetrating
peptides to the surface of nanoparticles [94] In-vivo studies in rats
showed that magnetic nanoparticles predominantly accumulate in
the liver and spleen after intravenous administration Jain et al [95]
studied the biodistribution clearance and biocompatibility of oleic
acidndashpluronic magnetic nanoparticles (MNPs) for in vivo biomedical
applications Changes in levels of alanine aminotransferase (ALT)
aspartate aminotransferase (AST) alkaline phosphatase (AKP) were
analyzed over 3 weeks after intravenous administration of MNPs to
rats They found that the serum iron levels gradually increased for up
to 1 week and then slowed down Greater fraction of the injected iron
is uptaken in liver and spleen which may be due to the increased
hydrodynamic diameter of the nanoparticles However histological
analyses of the organs showed no apparent abnormal changes
The energy-dependent cellular uptake of biocompatible 1047298uores-
cent (1047298uorescein isothiocyanate) mesoporous SiO2 nanoparticles
(FMSN) as well as the delivery of hydrophobic anticancer drug
paclitaxel to PANC-1 cancer cells were investigated [96] The cellular
uptake was higher at 37 degC than at 4 degC (Fig 3(a) and (b)) and
metabolic inhibitors such as sodium azide sucrose and ba1047297lomycin A
impeded the uptake of FMSN into cells These results suggested thatthe uptake was an energy-dependent endocytic process The uptake of
nanoparticles through energy-dependent endocytic process was also
observed with A549 and HeLa cells [9798]
In another study Guo et al [99] showed that the presence of ZnO
nanoparticles enhanced the cellular uptake of daunorubicin for
leukemia cell lines They have observed that the effective anti-drug
resistance and anticancer effect of photoexcited ZnO nanoparticles
accompanied with the anticancer drug shows synergistic cytotoxicity
suppression on leukemia cell lines under UV irradiation On the other
hand biocompatible ZnO nanocrystals having a non-centrosymmetric
structure was synthesized and used as non-resonant and nonlinear
optical probes for in vitro bioimaging applications [100] The
nanocrystals were dispersed in aqueous media using phospholipid
micelles and incorporated with the biotargeting folic acid (FA)
molecule The confocal images of KB cells treated with an aqueous
dispersion of ZnO and ZnO-FA (targeted by FA) for 1 and 3 h of
treatment shows robust intracellular signal (Fig 3(c) and (d))
In comparison to SiO2 and ZnO the cellular uptake of iron oxidenanoparticles and their nanocomposites were extensively explored
[45101] The cellular uptake of protein passivated-Fe3O4 nanoparti-
cles in different types of cancer cells was studied in the absence and
presence of serum [102] It was observed that the serum reduces the
cellular uptake of Fe3O4 nanoparticles and the internalization of
nanoparticles into cells takes place via endocytosis or by diffusion
penetration across the plasma membrane In another study the
cellular uptake and in vitro cytotoxicity of hollow mesoporous
spherical nanocomposites of Fe3O4SiO2 towards HeLa cells was
found relatively faster [103]
In an interesting study Pan et al [69] reported the development of
a nanoscale delivery system composed of MNPs coated with different
generation of PAMAM dendrimers (dMNP) and investigated the
uptake mechanism with different cell lines after complexing them
with antisense survivin oligodeoxynucleotides (asODN) They ob-
served that asODN-dendrimer-MNPs enter into tumor cells within
15 min (endocytosed by cancer cells Fig 4(a)) and inhibited cell
growth in dose- and time-dependent means The intracellular uptake
rate of G50 dMNP (1047297fth generation dMNP) was found to be 60
whereas that of naked MNPs was 10 (Fig 4(b))
Superparamagnetic iron oxide nanoparticles (SPIONs) have been
widely used in magnetic resonance imaging as they can be used as
contrast agent and can be incorporated into magnetic 1047297eld-guided
drug delivery carriers for cancer treatment However the hydropho-
bic nature of some SPION leads to fast reticuloendothelial system
(RES) uptake due to which their systemic administration still remains
a challenge Folate targeted NIPAAM-PEGMA composite magnetic
nanoparticles with imaging potential were reported [104] Co-
polymerisation of the nanocomposites with acrylic acid (AA) andpolyethylene glycol methacrylate (PEGMA) led to an increase in the
Curie temperature (TC) of the co-polymer to 44 degC enabling
hyperthermia coupled drug delivery The increased binding of the
PEGMA and AA with the iron surface caused prolonged circulation
time of the nanocomposites thereby preventing rapid clearance by
RES system The nanocomposites showed high T1 and T2 relaxivities
and R 1 and R 2 increases linearly with increase in iron concentration
proving their application for imaging purposes A dual imaging
(opticalMR) of Lewis lung carcinoma tumor by Cy55 conjugated
Fig 4 (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control without dMNP null MNP
without dendrimer modi1047297cation [69]) (Reproduced with permission from [69] copyright American Association for Cancer Research)
1274 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
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thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
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[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
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[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
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[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thermally crosslinked SPIONs in mice was studied [105] High level of
accumulation of these nanomagnets within the tumor site was
established by T2-weighted magnetic resonance images as well as in
optical 1047298uorescence images within 4 h of intravenous injection A
multifunctional Herceptin-conjugated Aurodsndash(Fe3O4)n wasstudied as
theranostic platforms for targeting SK-BR-3 cells (by MRI and
1047298uorescence) and destroying them (by Au-mediated photothermal
ablation) [106] In another work when a MRI contrast agent
containing targeted herceptinndashdextran coated magnetic nanoparticles
were administered to mice bearing breast tumor allograft the tumor
site was detected in T2-weighted MR images as a 45 enhancement
drop indicating a high level of accumulation of the contrast agent
within the tumor (Fig 5) The potential cytotoxicity of the herceptin-
nanoparticles indicated inhibition of cells that overexpress HER2neu
receptors (BT-474 SKBR-3 MDA-MB-231 and MCF-7) at high iron
concentrations [107]
Yang et al [108109] engineered urokinase plasminogen activator
receptor (uPAR) targeted biodegradable polymer coated magnetic
nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo
magnetic resonance and optical imaging in mouse mammary tumors
A strong magnetic resonance imaging contrast detectable by a clinical
MRI scanner at 1047297eld strength of 3 T was generated when ATF-IO was
systemically delivered into the mice bearing mammary tumors It was
also found that the mice administered with ATF-IO nanoparticles
Fig 5 T2-weighted images before andafter injection of herceptin-nanoparticlesA gray-level MRI B color-map MRI [107] (Reproduced with permission from [107] copyright Springer)
Fig 6 Targeting and in vivo magnetic resonance tumorimaging of intraperitoneal (ip) mammary tumorlesions Topbioluminescence imaging detects the presence of iptumors on
the upper right of the peritoneal cavity of the mouse MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or
30 h after the tail vein injection of 112 nmolkg of body weight [108] (Reproduced with permission from [108] copyright American Association for Cancer Research)
1275S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
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thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
[1] H Maeda J Wu T Sawa Y Matsumura K Hori Tumor vascular permeabilityand the EPR effect in macromolecular therapeutics a review J Control Rel 65(2000) 271ndash284
[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1015
exhibited lower uptake of the nanoparticles in liver and spleen as
compared with those receiving nontargeted iron oxide nanoparticles
(Fig 6)
42 Hyperthermia treatment of cancer
Functionalized MNPs and ferro1047298uids have been extensively used
for generating heat for magnetic hyperthermia treatment (MHT) as a
promising tool for therapeutics particularly for cancer With this heatmay be applied to tumor tissues with no systemic and side effects
compared to chemotherapy and radiotherapy In this application
MNPs are used as effective heating mediator in the presence of an
alternating current (AC) magnetic 1047297eld The type and thickness of
functional layers used for stabilizing nanoparticles can signi1047297cantly
in1047298uence heating ability The heat produced during MHT not only
destroys the tumor cells but also boosts the activity of the majority of
cytostatic drugs and activates the immunological response of the
body
Kim et al [110] reported that self-heating from MNPs under AC
magnetic 1047297eld can be used either for hyperthermia or to trigger the
release of an anti-cancer drug using thermo-responsive polymers
The heat generated by applying an AC magnetic 1047297eld depends on the
properties of MNPs (composition size shape and functionalization)
as well as the frequency and amplitude of the magnetic 1047297eld In their
study CoFe2O4 nanoparticles were investigated as heating agents for
hyperthermia and thermo-drug delivery Towards this approach our
research group has made signi1047297cant contributions in processing
functionalized MNPs of different ferrites and their ferro1047298uids Along
with CoFe2O4 we have investigated comparative heating ability as
well as biocompatibility of different ferrite based magnetic 1047298uids
[112224111ndash114] It has been observed that CoFe2O4 is rather toxic
compared to other Mn-based ferrites In vitro studies of water-based
ferro1047298uids of substituted ferrites Fe1minus xMn xFe2O4 [114] with an
average particle size of about 10ndash12 nm prepared by the co-
precipitation on BHK-21 cells showed that the threshold biocompat-
ible concentration is dependent on the nature of ferrite and their
surface modi1047297cation The reports showed that the value of speci1047297c
absorption rate (SAR) increased by 20 in Fe06Mn04Fe2O4 ascompared to Fe3O4 The higher SAR makes these materials useful for
hyperthermia applications The suspension of nanosized γ-Fe2O3 [25]
and γ-AlxFe2minus xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was
found suitable for hyperthermia treatment of cancer The mechanism
of cell death induced by magnetic hyperthermia with γ-MnxFe2ndashxO3
nanoparticles was 1047297rst investigated by our research group [26] The
hyperthermia induced by the application of an AC magnetic 1047297eld in
the presence of the Acrypol 934 stabilized γ-MnxFe2ndashxO3 suspension
caused the death of HeLa cells The cells showed varying degrees of
membrane blebbing with signi1047297cant disruption of the actin and
tubulin cytoskeletons (Fig 7) following MHT which 1047297
nally led to celldeath The cell death was proportional to the quantity of the particles
and the duration of the applied AC magnetic 1047297eld
Thermoresponsive polymer-coated magnetic nanoparticles can be
used for magnetic drug targeting followed by simultaneous hyperther-
mia and drug release Jaiswal et al [116] reported Poly(NIPAAm)-
chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4)
magnetic nanoparticles encapsulated magnetic nanohydrogels
(MNHGs) in which it has been observed that CS not only served as a
cross linker during polymerization but also plays a critical role in
controlling the growth of NHG and enhancement in lower critical
solution temperature (LCST) of poly(NIPAAm) which increased with
increasing weight ratio of CS to NIPAAm Also the presence of CS in the
composite makes it pH sensitive by virtue of which both temperature
andpH changes have been used to trigger drugrelease Furthermorethe
encapsulation of iron oxide nanoparticles into hydrogels also caused an
incrementin LCST Speci1047297cally temperature optimized NHGand MNHG
werefabricated havingLCST closeto 42 degC (hyperthermia temperature)
The MNHG shows optimal magnetization good speci1047297c absorption rate
(underexternalAC magnetic1047297eld)and excellent cytocompatibilitywith
L929 cell lines which may 1047297nd potential applications in combination
therapy involving hyperthermia treatment of cancer and targeted drug
delivery On a similar line of approach Meenach and coworkers [117]
demonstrated a method for remotely heating the tumor tissue using
hydrogel nanocomposites containing magnetic nanoparticles upon
exposure to an external alternating magnetic 1047297eld (AMF) Swelling
analysis of the systems indicated a dependence of ethylene glycol (EG)
content and cross-linking density on swelling behavior where greater
EG amount and lower cross-linking resulted in higher volume swelling
ratios Both the entrapped iron oxide nanoparticles and hydrogelnanocomposites exhibited high cell viability for murine 1047297broblasts
indicating potential biocompatibility The hydrogels were heated in an
AMF andthe heating response wasshownto be dependenton both iron
Fig 7 Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-MnxFe2minusxO3 [26] (Reproduced with permission from [26] copyright RSC publications)
1276 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1115
oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[2] JH Thrall Nanotechnology and medicine Radiology 230 (2004) 315ndash318[3] WB Tan S Jiang Y Zhang Quantum-dot based nanoparticles for targeted
silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
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[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1115
oxide loading in the gels and the strength of the magnetic 1047297eld The
thermal therapeutic ability of the hydrogel nanocomposites to selec-
tively kill M059K glioblastoma cells in vitro on exposure to an AMF has
been demonstrated
A unique drug delivery system based on mesoporous silica
nanoparticles and magnetic nanocrystals was developed [118] The
combined ability of the mesoporous silica nanoparticles to contain
and release cargos and the ability of the magnetic nanocrystals to
exhibit hyperthermic effects when placed in an oscillating magnetic1047297eld makes the system very promising Zinc-doped iron oxide
nanocrystals were incorporated within a mesoporous silica frame-
work and the surface was modi1047297ed with pseudorotaxanes Upon
application of an AC magnetic 1047297eld the nanocrystals generate local
internal heating causing the molecular machines to disassemble and
allowing the cargos (drugs) to be released Folic acid (FA) and
cyclodextrin (CD)-functionalized superparamagnetic iron oxide
nanoparticles FA-CD-SPIONs were synthesized by chemically
modifying SPIONs derived from iron (III) allylacetylacetonate and
the drug was incorporated [119] Heat generated by MNPs under
high-frequency magnetic 1047297eld (HFMF) is useful not only for
hyperthermia treatment but also as a driving force for the drug-
release Induction heating triggers drugrelease fromthe CD cavity on
the particlemdasha behavior that is controlled by switching the HFMF on
and off
MNPs coated with materials having unique properties such as
ordered pore structures and large surface areas hold great potential
for multimodal therapies Recently it has been reported [120] that
composites of maghemite nanoparticles embedded in an ordered
mesoporous silica-matrix forming magnetic microspheres (MMS)
have great abilityto induce magnetic hyperthermia uponexposure to
a low-frequency AMF MMS particles were ef 1047297ciently internalized
within human A549 Saos-2 and HepG2 cells and the MMStreatment
did not interfere with morphological features or metabolic activities
of the cells indicating good biocompatibility of the material
The in1047298uence of MNPs combined with short external AMF
exposure on the growth of subcutaneous mouse melanomas was
evaluated recently [121] Bimagnetic FeFe3O4 coreshell nanoparti-
cles were designed for cancer targeting after intratumoral orintravenous administration The inorganic core of the nanoparticles
was protected against rapid biocorrosion by organic dopamine-
oligoethylene glycol ligands The magnetic hyperthermia results
obtained after intratumoral injection indicated that micromolar
concentrations of iron given within the modi1047297ed corendashshell FeFe3O4
nanoparticles caused a signi1047297cant anti-tumor effect on melanoma
with three short 10-minuteAMFexposures Villanuevaet al[122] studied
the effect of a high-frequency AMF on HeLa tumor cells incubated with
ferromagnetic nanoparticles of manganese oxide perovskite La056(SrCa)022MnO3 The application of alternating electromagnetic 1047297eld
cells induced signi1047297cant cellular damage that 1047297nally caused cell death
by an apoptotic mechanism Cell death is triggered even though the
temperature increase in the cell culture during the hyperthermia
treatment is lower than 05 degC Another manganite La1ndashx AgxMnO3+ δ
has been explored as an alternative to superparamagnetic iron oxide
based particles for highly controllable hyperthermia cancer therapy
and imaging [123] Adjusting the silver doping level it was possible to
control the TC in the hyperthermia range of interest (41ndash44 degC) The
nanoparticles were found to be stable and their properties were not
affected by the typical ambient conditions in the living tissue When
placed in AMF the temperature of the nanoparticles increased to the
de1047297nite value near TC and then remained constant if the magnetic 1047297eld
is maintained During the hyperthermia procedure the temperature
can be restricted thereby preventing the necrosis of normal tissue
Recently we have demonstrated magnetic hyperthermia with biphasic
gel of La1minus xSr xMnO3 (LSMO) and γ -Al007 Fe193O3 [124] While LSMO
couldbe usefulfor self regulatingthe temperature the latter wasusedfor
better biocompatibility andhigher SAR values It has been observed that
SAR increases (time required to reach hyperthermia temperature
decreases) with increasing the ratio of Al-substituted maghemite
Such biphasic gel could be very useful for magnetic hyperthermia
with in vivo control of temperature La1minus xSrxMnO3 (LSMO)
nanoparticles were also stabilized by various polymers for biomedical
applications Prasad et al [125] fabricated acrypol stabilized Tc-tuned
biocompatible aqueous suspension of LSMO for magnetic hyperthermia
treatment of cancer with a possibility of in vivo temperature control
43 Other therapeutic applications
In recent years among host-guest hybrid materials layered
double hydroxides (LDH) have received much attention due to their
vast applicability and hence are considered to be the new generation
materials in areas such as nanomedicine [126] LDH materials having
bothcation and anion exchange properties provide an opportunity to
design a material with promising applications Pan et al [127]
established the importance of understanding the microstructure and
nature of LDH that could ultimately control the drug release
properties In their study a series of novel doxi1047298uridine intercalated
MgndashAl-layered double hydroxide (DFUR ndashLDH) microhybrids were
fabricated and diffusion controlled in-vitro release was observed An
anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH
[128] and it was further investigated for in vitro cytotoxicity to tumor
cells the cellular uptake and in vivo antitumor inhibition of PPT-LDH
The in vivo tests reveal that delivery of PPT via LDH nanoparticles is
moreef 1047297cient butthe toxicity to mice is reduced in PPT-LDH hybrids
in comparison with PPT alone These observations imply that LDH
nanoparticles are the potential carrier of anti-tumor drugs in a range
of new therapeutic applications The intercalation of sulfobutyl ether
β-cyclodextrin (SBE7-β-CD) into MgndashAl LDH was examined for
controlled release of prazosin a sympatholytic drug used to treat
high blood pressure [129] Anticancer drug podophyllotoxin (PPT)
[130] and campothecin [131] were encapsulated in the galleries of
MgndashAl LDH which showed that the drugndashinorganic composites can
be successfully used as drug delivery vehicle Cefazolin a cephalo-
sporin class antibacterial agent was also intercalated into LDH in
order to improve the drug ef 1047297ciency as well as to achieve thecontrolled release property [132] Recently the formation and
intercalation and stability of anti-cardiovascular drugs (pravastatin
and 1047298uvastatin) in [Fe(CN)6]3minus based Ni2+Fe3+ LDH was studied
[133] Structural characterization techniques revealed that the
1047298uvastatin anions are attached with the brucite as a monolayer
whereas the pravastatin anions form a multilayer In vitro release
study of nanohybrid particles suggested that there is a signi1047297cant
reduction in release rate of 1047298uvastatin anions from 1047298uvastatin
intercalated LDHs which may probably be due to its hydrophobic
nature however it can be controlled by varying the concentration in
physiological medium The advantage of this method is that the
excess divalent metal ions in LDHs can be used as high-temperature
inorganic surfactant to restrict the growth and agglomeration of
MNPs by forming a divalent oxide protective layer on the surfaceduring heat treatment
44 Towards clinical trials
Though cancer is a pervasive problem the improvement in
technologies in diagnosis and treatments has signi1047297cantly decreased
themortality rates all over theworld It may be possibleto detect the
cancer at an early stage with the use of nanodevices when the initial
molecular changes start occurring at the nanoscale level inside the
cells Thus thescenario for treatment of cancer is completely changed
in most of the cancers if detected early After diagnosis nanoscale
devices can potentially improve cancer therapy over conventional
chemotherapy and radiotherapy Cancer drugs being mostly cyto-
toxic to both healthy and cancer cells cause severe side effects
1277S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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silencing of HER2neu gene via RNA interference Biomaterials 28 (2007)1565ndash1571
[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
is size-dependent Nat Nanotechnol 3 (2008) 145ndash
150
1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
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[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
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[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1215
thereby limiting the ef 1047297cacy of chemotherapy [134] Therefore it
becomes necessary to develop drug formulations which can
transport the toxic drug speci1047297cally to the cancer cells and release
them in a timely and controlled manner Advancement in nanotech-
nology has opened up opportunities to nanodevices especially in
developing new therapeutic formulations for improved cancer drug
delivery The nanodevices cannot only be used in the area of
multifunctional therapeutics (ie to create therapeutic devices
which control the release of cancer drugs and deliver medicationoptimally) but also to cancer prevention and control early detection
and imaging diagnostics Several engineered nanoparticulates in-
volving dendrimers liposomes or other macromolecules aretargeted
to cancer cells which increase the selectivity of the drug towards
cancer cells thereby reducing toxicity to the normal cells This is
normally done by attaching monoclonal antibodies or receptor
ligands that speci1047297cally bind to the cancer cells Research on folate
conjugated nanoparticles showed high speci1047297city for human cancer
cells and an improved drug uptake [135] Conjugation of FITC
(imaging agent) folic acid (targeting molecule) and paclitaxel
(drug) to a dendrimer and their in vitro targeted delivery to cancer
cells has been discussed [136] It was found that the cells containing
thefolic acid receptor took up the dendrimer whichhad a toxic effect
while the dendrimers had no effect on the cells without folic acid
receptor Liposomal nanodevices are extensively investigated as
harmless drug delivery carriers which not only carry 1047297xed dose of
anti cancer drug combinations but also circulate in the blood stream
for a longer time [137138] Substantial improvements in using the
magnetic nanoparticles for clinical applications such as drug
delivery MRI magnetic drug targeting and hyperthermia has been
made in the recent past However the clinical breakthrough was
achieved by Maier-Hauff et al [139] in 2007 when deep cranial
thermotherapy using magnetic nanoparticles was safely applied to
14 glioblastoma multiforme patients The patients were intratumo-
rally injected with theiron oxide nanoparticles and exposed to an AC
magnetic 1047297eld to induce particle heating MRI was followed to
evaluate the amount of 1047298uid and spatial distribution of the depots
and the actually achieved magnetic 1047298uid distribution was measured
by computed tomography Patients were tolerant to thermotherapyand minor or no side effects were observed In a recent clinical trial
[140] insterstitial heating of tumors following direct injection of
magnetic nanoparticles has been carried out for the treatment of
prostate cancer However patient discomfort at high magnetic 1047297eld
and irregular intratumoral heat distribution remained the limiting
factor of thetrialsJohannsenet al [141] reported theresultsof phase
I clinical trial using magnetic nanoparticles involving 10 patients
with locally recurrent prostate cancer No systemic toxicity was
observed at a median follow-up of 175 months and prostate speci1047297c
antigen (PSA) were found to reduce however acute urinary
retention occurred in four patients with previous history of urethral
retention Although there are a number of successful phase I clinical
trials based on therapeutic magnetic targeting very little successful
clinical translations has come up [142143] Landeghem et al [144]demonstrated the tolerability and anti-tumoral effect of thermo-
therapy using magnetic nanoparticles and the ef 1047297cacy of magnetic
1047298uid hyperthermia (MFH) in murine model of malignant glioma
which is under evaluation for phase II study From brain autopsies it
was found that the instillation of magnetic nanoparticles for MFH in
patients result in uptake of nanoparticles in glioblastoma cells to a
minor extent andin macrophages to a major extent as a consequence
of tumor inherent and therapy induced formation of necrosis with
subsequent in1047297ltration and activation of phagocytes Intracranial
thermotherapy using aminosilane magnetic nanoparticles were
performed on 14 patients who were then exposed to an AC magnetic
1047297eld All the patients tolerated instillation of the nanoparticles
without any complications and the ef 1047297cacy of the treatment is under
evaluation in phase II study [145]
5 Conclusion and future scope
The developing market in this decade has already seen the use of
nanotechnology to develop ef 1047297cient drug delivery system The next
evolution will be using nanotechnology for in vivo uses such as
implanting multifunctional particles in biological tissue to deliver
medicine destroy tumors and stimulate immune responses Some of
these multifunctional nano-sized assemblies can act as biological
systems working together and holds immense potential for cancertherapy and diagnostics These approaches will encompass the
desired goals of early detection tumour regression with limited
collateral damages and ef 1047297cient monitoring of response to chemo-
therapy In the foreseeable future the most important clinical
application of nanotechnology will probably be in pharmaceutical
development These applications take advantage of the unique
properties of nanoparticles as drugs or constituents of drugs or are
designed for new strategies to stabilize drugs and their control
release drug targeting and salvage of drugs with low bioavailability
Although the nanosized materials can be useful in medicine but
they can be potentially dangerous to human body as far as the toxicity
of the nanocarriersnanocomposites is concerned The nanomaterials
have unrestricted access to the human body and have the ability to
pass through the blood brain barrier thereby evading their detection
by the bodys immune system Usually foreign substances are
absorbed by phagocytes once they enter the blood stream however
any substance in the nanoscale range is no longer absorbed by the
phagocytes and thus they travel though the blood and move
randomly throughout the body Within this physiological compart-
mentthe nanomaterials may interact with cell populationresulting in
internalization through receptor-mediated endocytosis phagocytosis
and pinocytosis The materials remain in the endosomes and
accumulate within the organs and its eventual localization dictates
their toxicity
Despite immense impact of nanomedicines in cancer societal
implications cannot be overlooked The danger of derailing nanome-
dicines alwaysexists if thescience leaps ahead of the ethical legal and
social implications It is of utmost importance that the area of
nanotechnology pays attention not only to the making of devices andprocesses but also to the psychological and social aspect as a part of
any development
Futuristic nanotechnology will also see medical implants as
another sector for better biomedical implants such as a small active
pacemaker Besides all the developments the exciting milestones
made in these areas need to be paralleled with safety evaluations of
the platforms before they are translated to the clinics Nevertheless
we believe that the next few years are likely to see an increasing
number of nanotechnology-based therapeutics and diagnostics reach-
ing the clinic
Acknowledgements
The 1047297nancial support by Nanomission of Department of Science
and Technology and Department of Information Technology Govt of
India is gratefully acknowledged
References
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[4] W JiangBY Kim JT Rutka WC ChanNanoparticle mediated cellular response
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1278 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
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[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
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[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
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[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
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induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
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particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
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stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
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[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
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in the micron size range Coll Interf Sci 26 (1968) 62ndash
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[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
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discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
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[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
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[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
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[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
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nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
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delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
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J Pharma 365 (2009) 180ndash189
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Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1315
[5] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[6] DA LaVan T McGuire R Langer Small-scale systems for in vivo drug deliveryNat Biotechnol 21 (2003) 1184ndash1191
[7] B Reinhard S Sheikholeslami A Mastroianni AP Alivisatos J Liphardt Use of plasmon coupling to reveal the dynamics of DNA bending and cleavage by singleEcoRV restriction enzymes Proc Natl Acad Sci USA 104 (2007) 2667 ndash2672
[8] NL Rosi CA Mirkin Nanostructures in biodiagnostics Chem Rev 105 (2005)1547ndash1562
[9] H Cheng CJ Kastrup R Ramanathan DJ Siegwart M Ma SR Bogatyrev Q Xu
KA Whitehead R Langer DG Anderson Nanoparticulate cellular patches forcell-mediated tumoritropic delivery ACS Nano 4 (2010) 625ndash631[10] D Bahadur J Giri Biomaterials and magnetism Sadhana 28 (2003) 639ndash656[11] P Pradhan J Giri R Banerjee J Bellare D Bahadur Preparation and
characterizations of manganese ferrite based magnetic liposomes for hyper-thermia treatment of cancer J Magn Magn Mater 311 (2007) 208ndash215
[12] V Bagalkot L Zhang E Levy-Nissenbaum Quantum dot-aptamer conjugates forsynchronous cancer imaging therapy and sensing of drug delivery based on bi-1047298uorescence resonance energy transfer Nano Lett 7 (2007) 3065ndash3070
[13] DA LaVan DM Lynn R Langer Moving smaller in drug discovery and deliveryNat Rev Drug Discovery 1 (2002) 77ndash84
[14] HS Panda R Srivastava D Bahadur In-Vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B113 (2009) 15090ndash15100
[15] J Chen F Saeki BJ Wiley Gold nanocages bioconjugation and their potentialuse as optical imaging contrast agents Nano Lett 5 (2005) 473ndash477
[16] AM Gobin MH Lee NJ Halas WD James RA Drezek JL West Near-infraredresonant nanoshells for combined optical imaging and photothermal cancertherapy Nano Lett 7 (2007) 1929ndash1934
[17] A Fu W Gu B Boussert Semiconductor quantum rods as single molecule1047298uorescent biological labels Nano Lett 7 (2007) 179ndash182
[18] Y Xing Q Chaudry C Shen Bioconjugated quantum dots for multiplexed andquantitative immunohisto chemistry Nat Protoc 2 (2007) 1152ndash1165
[19] ER Goldman GP Anderson PT Tran H Mattoussi PT Charles JM MauroConjugation of luminescent quantum dots with antibodies using an engineeredadaptor protein to provide new reagents for 1047298uoroimmunoassays Anal Chem74 (2002) 841ndash847
[20] M Gupta A Caniard A Touceda-Varek DJ Campopiano JC Mareque-RivasNitrilotriacetic acid-derivatized quantum dots for simple puri1047297cation and site-selective 1047298uorescent labeling of active proteins in a single step Bioconj Chem19 (2008) 1964ndash1967
[21] M HowarthK Takeo Y KayashiAY Ting Targeting quantumdotsto surfaceproteinsin living cells with biotin ligase Proc Natl Acad Sci USA 102 (2005) 7583ndash7588
[22] KC Barick M Aslam Y-P Lin D Bahadur PV Prasad VP Dravid Novel andef 1047297cient MR active aqueous colloidal Fe3O4 nanoassemblies J Mater Chem 19(2009) 7023ndash7029
[23] AK Gupta M Gupta Synthesis and surface engineering of iron oxidenanoparticles for biomedical applications Biomaterials 26 (2005) 3995ndash4021
[24] P Pradhan J Giri G Samanta HD Sarma KP Mishra J Bellare R Banerjee DBahadur Comparative evaluation of heating ability and biocompatibility of different ferrite-based magnetic 1047298uids for hyperthermia application J BiomedMater Res B Appl Biomater (2006) 12ndash22
[25] NK Prasad D Panda S Singh MD Mukadam SM Yusuf D BahadurBiocompatible suspension of nanosized γ-Fe2O3 synthesized by novel methods
J Appl Phys 97 (10Q903) (2005) 1ndash3[26] NK Prasad K Rathinasamy D Panda D Bahadur Mechanism of cell death
induced by magnetic hyperthermia with nanoparticles of γ-Mn xFe2ndash xO3
synthesized by a single step process J Mater Chem 17 (2007) 5042ndash5051[27] M Longmire PL Choyke H Kobayashi Clearance properties of nano-sized
particles and molecules as imaging agents considerations and caveatsNanomedicine 3 (2008) 703ndash717
[28] P Decuzzi F Causa M Ferrari PA Netti The effective dispersion of nanovectorswithin the tumor microvasculature Annals Biomed Eng 34 (2006) 633ndash641
[29] JH Park G von Maltzahn L Zhang AM Derfus D Simberg TJ Harris ERuoslahti SN Bhatia MJ Sailor Systematic surface engineering of magneticnanoworms for in vivo tumor targeting Small 5 (2009) 694ndash700
[30] IISlowingJL Vivero-EscotoBG TrewynVS-Y LinMesoporous silicananoparticlesstructural design and applications J Mater Chem 20 (2010) 7924ndash7937
[31] T Osaka T Nakanishi S Shanmugam S Takahama H Zhang Effect of surfacecharge of magnetite nanoparticles on theirinternalization into breast cancer andumbilical vein endothelial cells Coll Surf B Biointerf 71 (2009) 325ndash330
[32] KC Barick M Aslam PV Prasad VP Dravid D Bahadur Nanoscale assembly of amine functionalized colloidal iron oxide J Magn Magn Mater 321 (2009)1529ndash1532
[33] C Boyer MR Whittaker V Bulmus J Liu TP Davis The design and utility of polymer stabilized iron oxide nanoparticles for nanomedicine applications NPGAsia Mater 2 (2010) 23ndash30
[34] FQ Hu L Wei Z Zhou YL Ran Z Li MY Gao Preparation of biocompatiblemagnetite nanocrystals for in vivo magnetic resonance detection of cancer AdvMater 18 (2006) 2553ndash2556
[35] Y FuX DuAK SergeiJ Qiu W Qin R LiJ Sun JLiu Stableaqueous dispersionof ZnO quantum dots with strong blue emission via simple solution route J AmChem Soc 129 (2007) 16029ndash16033
[36] E Munnier S Cohen-Jonathan C Linassier L Douziech-Eyrolles H Marchais MSouceacute K Herveacute P Dubois I Chourpa Novel method of doxorubicin-SPION
reversible association for magnetic drug targeting Int J Pharma 361 (2008)170ndash176
[37] Y Lai W Yin J Liu R Xi J Zhan One-pot green synthesis and bioapplication of L -arginine-capped superparamagnetic Fe3O4 nanoparticles Nanoscale Res Lett5 (2009) 302ndash307
[38] J Xie K Chen H-Y Lee C Xu AR Hsu S Peng X Chen S Sun Ultrasmallc(RGDyK)-coated Fe3O4 nanoparticles and their speci1047297c targeting to integrinαvβ3-rich tumor cells J Am Chem Soc 130 (2008) 7542ndash7543
[39] CRA Valois JM Braz ES Nunes MAR Vinolo ECD Lima R Curi WMKuebler RB Azevedo The effect of DMSA-functionalized magnetic nanoparti-cles on transendothelial migration of monocytes in the murine lung via a β2
integrin-dependent pathway Biomaterials 31 (2010) 366ndash
374[40] L Maurizi H Bisht F Bouyer N Millot Easy route to functionalize iron oxidenanoparticles via long-term stable thiol groups Langmuir 25(2009) 8857ndash8859
[41] JK Lim SA Majetich RD Tilton Stabilization of superparamagnetic iron oxidecorendash gold shell nanoparticles in high ionic strength media Langmuir 25 (2009)13384ndash13393
[42] J Xie C Xu N Kohler Y Hou S Sun Controlled PEGylation of monodisperseFe3O4 nanoparticles for reduced non-speci1047297c uptake by macrophage cells AdvMater 19 (2007) 3163ndash3166
[43] SJH Soenen M Hodenius T Schmitz-Rode M De Cuyper Protein stabilizedmagnetic 1047298uids J Magn Magn Mater 320 (2008) 634ndash641
[44] F Yu VC Yang Size-tunable synthesis of stable superparamagnetic iron oxidenanoparticles for potential biomedical applications J Biomed Mater Res A 92(2010) 1468ndash1475
[45] P Pradhan J Giri R BanerjeeJ Bellare D Bahadur Cellular interactionsof lauricacid and dextran-coated magnetite nanoparticles J Magn Magn Mater 311(2007) 282ndash287
[46] J Zhang RDK Misra Magnetic drug-targeting carrier encapsulated withthermosensitive smart polymer corendashshell nanoparticle carrier and drugrelease
response Acta Biomater 3 (2007) 838ndash850[47] JE Wong AK Gaharwar D Muumlller-Schulte D Bahadur W Richtering Dual-
stimuli responsive PNiPAM microgel achieved via layer-by-layer assemblymagnetic and thermoresponsive J Coll Interf Sci 324 (2008) 47 ndash54
[48] JE Wong AK Gaharwar D Muller-Schulte D Bahadur W Richtering Layer-by-layer assembly of magnetic nanoparticles shell on thermoresponsivemicrogel core J Magn Magn Mater 311 (2007) 219ndash223
[49] SG Hirsch RJ Spontak Temperature-dependent property development inhydrogels derived from hydroxypropylcellulose Polymer 43 (2002) 123ndash129
[50] MD Determan JP Cox S Seifert P Thiyagarajan SK Mallapragada Synthesisand characterization of temperature and pH-responsive pentablock copolymersPolymer 46 (2005) 6933ndash6946
[51] K Letchford H Burt A review of the formation and classi1047297cation of amphiphilicblock copolymer nanoparticulate structures micelles nanospheres nanocap-sules and polymerosomes Eur J Pharm Biopharm 65 (2007) 259ndash269
[52] P Chandrasekharan D Maity Y Chang-Tong C Kai-Hsiang J Ding F Si-ShenSuperparamagnetic iron oxide-loaded poly (lactic acid)-D-α-tocopherol poly-ethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agentBiomaterials 31 (2010) 5588ndash5597
[53] PV Finotelli D Da Silva M Sola-Penna AM Rossi M Farina LR Andrade AYTakeuchi MH Rocha-Leao Microcapsules of alginatechitosan containingmagnetic nanoparticles for controlled release of insulin Coll Surfaces BBiointerf 81 (2010) 206ndash211
[54] S Theerdhala D Bahadur S Vitta N Perkas Z Zhong A GedankenSonochemical stabilization of ultra1047297ne colloidal biocompatible magnetitenanoparticles using amino acid L-arginine for possible bio applicationsUltrason Sonochem 17 (2009) 730ndash737
[55] Y-C Chiu Y-C Chen Carboxylate-functionalized iron oxide nanoparticles insurface-assisted laser desorptionionization mass spectrometry for the analysisof small biomolecules Anal Lett 41 (2008) 260ndash267
[56] JME Khoury D Caruntu CJ OConnor K-U Jeong SZD Cheng J Hu Poly(allylamine) stabilized iron oxide magnetic nanoparticles J Nanopart Res 9(2007) 959ndash964
[57] Y Ge Y Zhang J Xia M Ma S He F Nie N Gu Effect of surface charge andagglomerate degree of magnetic iron oxide nanoparticles on KB cellular uptakein vitro Coll Surf B 73 (2009) 294ndash301
[58] W Stoumlber A Fink EJ Bohn Controlled growth of monodisperse silica spheres
in the micron size range Coll Interf Sci 26 (1968) 62ndash
69[59] Y Zhang SWY Gong L Jin SM Li ZP Chen M Ma N Gu Magnetic
nanocomposites of Fe3O4SiO2-FITC with pH-dependent 1047298uorescence emissionChinese Chem Lett 20 (2009) 969ndash972
[60] CWLaiYHWang CH Lai MJ YangCYChenPTChou CS ChanY Chi YCChen JK Hsiao Iridium-complex-functionalized Fe3O4SiO2 coreshell nano-particles a facile three-in-one system in magnetic resonance imagingluminescence imaging and photodynamic therapy Small 4 (2008) 218ndash224
[61] J Giri A Ray S Dasgupta D Datta D Bahadur Investigations on TC tuned nanoparticles of magnetic oxidesfor hyperthermiaapplications Biomed Mater Engg13 (2003) 387ndash399
[62] Z Xu Y Hou S Sun Magnetic coreshell Fe3O4Au and Fe3O4AuAgnanoparticles with tunable plasmonic properties J Am Chem Soc 129(2007) 8698ndash8699
[63] U Tamer Y Guumlndoğdu İH Boyac K Pekmez Synthesis of magnetic corendashshellFe3O4ndashAu nanoparticle for biomolecule immobilization and detection JNanopart Res 12 (2009) 1187ndash1196
[64] C Xu B Wang S Sun Dumbbell-like AundashFe3O4 nanoparticles for target-speci1047297cplatin delivery J Am Chem Soc 131 (2009) 4216ndash4217
1279S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1415
[65] N Nasongkla E Bey JM Ren H Ai C Khemtong JS Guthi SF Chin ADSherry DA Boothman JM Gao Multifunctional polymeric micelles as cancer-targeted MRI-ultrasensitive drug delivery systems Nano Lett 6 (2006)2427ndash2430
[66] P Pradhan J Giri F Rieken C Koch O Mykhaylyk M Doumlblinger R Banerjee DBahadur C Plank Targeted temperature sensitive magnetic liposomes forthermo-chemotherapy J Control Rel 142 (2010) 108ndash121
[67] MS Martina JP Fortin C Menager O Clement G Barratt C Grabielle-Madelmont F Gazeau V Cabuil S Lesieur Generation of superparamagneticliposomesrevealed as highly ef 1047297cientMRI contrastagents for in vivo imagingJAm Chem Soc 127 (2005) 10676ndash10685
[68] J Giri SG Thakurta J Bellare AK Nigam D Bahadur Preparation andcharacterization of phospholipid stabilized uniform sized magnetite nanopar-ticles J Magn Magn Mater 293 (2005) 62ndash68
[69] BPanD Cui YSheng COzkan FGaoR HeQ LiP XuT HuangDendrimer-modi1047297ed magnetic nanoparticles enhance ef 1047297ciency of gene delivery systemCancer Res 67 (2007) 8156ndash8163
[70] S Chandra S Mehta S Nigam D Bahadur Dendritic magnetite nanocarriers fordrug delivery applications New J Chem 34 (2010) 648ndash655
[71] O Taratula O Garbuzenk R Savla YA Wang H He T Minko Multifunctionalnanomedicine platform for cancerspeci1047297c deliveryof siRNA by superparamagneticiron oxide nanoparticlesndashdendrimer complexes Curr Drug Deliv 8 (2011) 59ndash69
[72] JW Bulte T Douglas B Witwer SC Zhang BK Lewis P van Gelderen HZywicke ID Duncan JA Frank Monitoring stem cell therapy in vivo usingmagnetodendrimers as a newclass of cellularMR contrastagents Acad Radiol9 (2002) S332ndashS335
[73] JE WongAK GaharwarD Muumlller-Schulte D Bahadur W RichteringMagneticnanoparticlendashpolyelectrolyte interaction a layered approach for biomedicalapplications J Nanosci Nanotechnol 8 (2008) 4033ndash4040
[74] G Oberdorster E Oberdorster J Oberdorster Nanotoxicology an emerging
discipline evolving from studies of ultra1047297ne particles Environ Health Pers 113(2005) 823ndash839
[75] CM Boubeta L Balcells R Cristogravefol C Sanfeliu E Rodriacuteguez R Weissleder SLope-Piedra1047297ta K Simeonidis M Angelakeris F Sandiumenge A Calleja LCasas C Monty B Martiacutenez Self-assembled multifunctional FeMgO nano-spheres for magnetic resonance imaging and hyperthermia NanomedNanotechnol Bio Med 6 (2010) 362ndash370
[76] M Mahmoudi MA Shokrgozar A Simchi M Imani AS Milani P Stroeve HValiUO HafeliS Bonakdar Multiphysics1047298owmodelingand invitro toxicityof iron oxide nanoparticles coated with poly(vinyl alcohol) J Phy Chem C 113(2009) 2322ndash2331
[77] T Kikumori T Kobayashi M Sawaki T Imai Anti-cancer effect of hyperther-mia on breast cancer by magnetite nanoparticle-loaded anti-HER2 immuno-liposomes Breast Cancer Res Treat 113 (2009) 435ndash441
[78] CG Hadjipanayis R Machaidze M Kaluzova L Wang AJ Schuette H Chen XWu H Mao EGFRvIII antibody-conjugated iron oxidenanoparticles for magneticresonance imaging-guided convection-enhanced delivery and targeted therapyof glioblastoma Cancer Res 70 (2010) 6303ndash6312
[79] X Du J He Elaborate control over the morphology and structure of mercapto-functionalized mesoporous silica as multipurpose carriers Dalton Trans 39(2010) 9063ndash9072
[80] S Ma Y Wang Y Zhu A simple room temperature synthesis of mesoporoussilica nanoparticles for drug storage and pressure pulsed delivery J PorousMater 18 (2010) 233ndash239
[81] M Bikram AM Gobin RE Whitmire JL West Temperature-sensitivehydrogels with SiO2ndashAu nanoshells for controlled drug delivery J Cont Rel123 (2007) 219ndash227
[82] KC Barick S Nigam D Bahadur Nanoscale assembly of mesoporous ZnO apotential drug carrier J Mater Chem 20 (2010) 6446ndash6452
[83] Q Yuan S Hein RDK Misra New generation of chitosan-encapsulated ZnOquantum dots loaded with drug synthesis characterization and in vitro drugdelivery response Acta Biomater 6 (2010) 2732ndash2739
[84] J Li D Guo X Wang H Wang H Jiang B Chen The photodynamic effect of different size ZnO nanoparticles on cancer cell proliferation in vitro NanoscaleRes Lett 5 (2010) 1063ndash1071
[85] S Nigam KC Barick D Bahadur Development of citrate-stabilized Fe3O4
nanoparticles Conjugation and release of doxorubicin for therapeutic
applications J Magn Magn Mater 323 (2011) 237ndash
243[86] K Cheng S Peng C Xu S Sun Porous hollow Fe3O4 nanoparticles for targeted
delivery and controlled release of cisplatin J Am Chem Soc 131 (2009)10637ndash10644
[87] T Hoare J Santamaria GF Goya Irusta Silvia Lin Debora S Lau R Padera RLanger DS Kohane A magnetically triggered composite membrane for on-demand drug delivery Nano Lett 9 (2009) 3651ndash3657
[88] M Rahimi A Wadajkar K Subramanian M Yousef W Cui J-T Hsieh KTNguyen In vitro evaluation of novel polymer-coated magnetic nanoparticles forcontrolled drug delivery Nanomed Nanotechnol Biol Med 6 (2010) 672ndash680
[89] J ZhangS Rana RS Srivastava RDKMisra On thechemical synthesisand drugdelivery response of folate receptor-activated polyethylene glycol-functiona-lized magnetite nanoparticles Acta Biomater 4 (2008) 40ndash48
[90] J Qia P Yao F He C Yu C Huang Nanoparticles with dextranchitosan shelland BSAchitosan corendashDoxorubicin loading and delivery Int J Pharma 393(2010) 176ndash184
[91] B Gaihre MS Khil DR Lee HY Kim Gelatin-coated magnetic iron oxidenanoparticles as carrier system drug loading and in vitro drug release study Int
J Pharma 365 (2009) 180ndash189
[92] RAL Jones Soft Mashines Nanotechnology and Life Oxford University Press2004
[93] JR McCarthy R Weissleder Multifunctional magnetic nanoparticles fortargeted imaging and therapy Adv Drug Deliv Rev 60 (2008) 1241ndash1251
[94] MJ Pittet PK Swirski F Reynolds L Josephson R Weissleder Labelling of immune cells for in vivo imaging using magneto1047298uorescent nanoparticles NatProtoc 1 (2006) 73ndash79
[95] TK Jain MK Reddy MA Morales DL Leslie-Pelecky V LabhasetwarBiodistribution clearance and biocompatibility of iron oxide magnetic nano-particles in rats Mol Pharma 5 (2008) 316ndash327
[96] J Lu M Liong S Sherman T Xia M Kovochich AE Nel JI Zink F Tamanoi
Mesoporous silica nanoparticles for cancer therapy energy-dependent cellularuptake and delivery of paclitaxel to cancer cells Nanobiotechnol 3 (2007) 89ndash95[97] JS Kim TJ Yoon KN Yu MS Noh M Woo BG Kim Cellular uptake of
magnetic nanoparticle is mediated through energy-dependent endocytosis inA549 cells J Vet Sci 7 (2006) 321ndash326
[98] X Xing X He J Peng K Wang W Tan Uptake of silica-coated nanoparticles byHeLa cells J Nanosci Nanotechnol 5 (2005) 1688ndash1693
[99] D Guo C Wu H Jiang Q Li X Wang B Chen Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancercells under UV irradiation J Photochem Photobio B 93 (2008) 119ndash126
[100] AV Kachynski AN Kuzmin M Nyk I Roy PN Prasad Zinc oxide nanocrystalsfor nonresonant nonlinear optical microscopy in biology and medicine J PhysChem C 112 (2008) 10721ndash10724
[101] K Woo J Moon K-S Choi T-Y Seong K-H Yoon Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles J MagnMagn Mater 321 (2009) 1610ndash1612
[102] A Bajaj B Samanta H Yan DJ Jerry VM Rotello Stability toxicity anddifferential cellular uptake of protein passivated-Fe3O4 nanoparticles J MaterChem 19 (2009) 6328ndash6331
[103] Y Zhu T Ikoma N Hanagata S Kaskel Rattle-type Fe3O4SiO2 hollowmesoporous spheres as carriers for drug delivery Small 6 (2010) 471 ndash478
[104] R Rastogia N Gulatia RK Kotnala U Sharma R Jayasundar V Koul Evaluationof folate conjugated pegylated thermosensitive magnetic nanocomposites fortumor imaging and therapy Coll Surf B Biointerf 82 (2011) 160ndash167
[105] W-S Cho M Cho SR Kim M Choi JY Lee BS Han SN Park MK Yu S Jon J Jeong Pulmonary toxicity and kinetic study of Cy55-conjugated superpara-magnetic iron oxide nanoparticles by optical imaging Toxicol Appl Pharmacol239 (2009) 106ndash115
[106] C Wang J Chen T Talavage J Irudayaraj Gold nanorodFe3O4 nanoparticleldquoNano-pearl-necklacesrdquo for simultaneous targeting dual-mode imaging andphotothermal ablation of cancer cells Angew Chem Int Ed 48 (2009)2759ndash2763
[107] T-J Chen T-H Cheng C-Y Chen SCN Hsu T-L Cheng G-C Liu Y-M WangTargeted herceptinndashdextran iron oxide nanoparticles for noninvasive imaging of HER2neu receptors using MRI J Biol Inorg Chem 14 (2009) 253 ndash260
[108] L Yang X-H Peng YA Wang X Wang Z Cao C Ni P Karna X Zhang WCWoodX Gao S Nie H Mao Receptor-targeted nanoparticles for in vivo imagingof breast cancer Clin Cancer Res 15 (2009) 4722ndash4732
[109] L Yang Z Cao HK Sajja H Mao L Wang H Geng H Xu T Jiang WC Wood SNie YA Wang Development of receptor targeted magnetic iron oxidenanoparticles for ef 1047297cient drug delivery and tumor imaging J BiomedNanotechnol 4 (2008) 439ndash449
[110] D-H Kim DE Nikles DT Johnson CS Brazel Heat generation of aqueouslydispersed CoFe2O4 nanoparticles as heating agents for magnetically activateddrug delivery and hyperthermia J Magn Magn Mater 320 (2008)2390ndash2396
[111] J Giri D Bahadur Novel ferro1047298uids preparation Indian patent 475mum20042004
[112] J Giri T Sriharsha TK Gundu Rao D Bahadur Synthesis of capped nano sizedMn1minusxZnxFe2O4 (0lexle08) by microwave re1047298uxing for bio-medical applica-tions J Magn Magn Mater 293 (2005) 55ndash61
[113] J Giri P Pradhan V Somani H Chelawat S Chhatre R Banerjee D BahadurSynthesis and characterizations of water-based ferro1047298uids of substituted ferrites[Fe1minusx BxFe2O4B = MnC o( x = 0ndash1)] for biomedical applications J Mag MagnMat 320 (2008) 724ndash730
[114] J Giri P Pradhan T Sriharsha D Bahadur Preparation and investigation of
potentiality of different soft ferrites for hyperthermia applications J Appl Phys10Q916 (2005) 1ndash3
[115] NK Prasad D Panda S Singh D Bahadur Preparation of cellulose-basedbiocompatible suspension of nano-sized γ-AlxFe2minusx O3 IEEE Trans Magnetics41 (2005) 4099ndash4101
[116] MK Jaiswal R Banerjee P Pradhan D Bahadur Thermal behavior of magnetically modalized poly(N-isopropylacrylamide)-chitosan based nanohy-drogel Coll Surf B Biointerf 81 (2010) 185ndash194
[117] SA Meenach JZ Hilt KW Anderson Poly(ethylene glycol)-based magnetichydrogel nanocomposites for hyperthermia cancer therapy Acta Biomater 6(2010) 1039ndash1046
[118] CR Thomas DP Ferris J-H Lee E Choi MH Cho ES Kim JF Stoddart J-SShin J Cheon JI Zink Noninvasive remote-controlled release of drug moleculesin vitro using magnetic actuation of mechanized nanoparticles J Am Chem Soc132 (2010) 10623ndash10625
[119] KHayashiK Ono H Suzuki M Sawada M Moriya WSakamotoT Yogo High-frequency magnetic-1047297eld-responsive drug release from magnetic nanoparticleorganic hybrid based on hyperthermic effect Appl Mater Interf 2 (2010)1903ndash1911
1280 S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281
8132019 Oxide and Hybrid Nanostructures for Therapeutic Apps
httpslidepdfcomreaderfulloxide-and-hybrid-nanostructures-for-therapeutic-apps 1515
[120] FM Martiacuten-Saavedra E Ruiacutez-Hernaacutendez A Boreacute D Arcos M Vallet-Regiacute NVilaboa Magnetic mesoporous silica spheres for hyperthermia therapy ActaBiomater 6 (2010) 4522ndash4531
[121] S Balivada RS Rachakatla H Wang TN Samarakoon RK Dani M Pyle FOKroh B Walker X Leaym OB Koper M Tamura V Chikan SH Bossmann DLTroyer AC magnetic hyperthermia of melanoma mediated by iron(0)ironoxide coreshell magnetic nanoparticles a mouse study BMC Cancer 10 (2010)119ndash127
[122] A Villanueva P de la Presa JM Alonso T Rueda A Martiacutenez P Crespo MPMorales MA Gonzalez-Fernandez J Valdeacutes G Rivero Hyperthermia HeLa celltreatment with silica-coated manganese oxide nanoparticles J Phys Chem C
114 (2010) 1976ndash
1981[123] OV Melnikov OYu Gorbenko MN Ma rkelova AR Kaul VA Atsarkin VVDemidov C Soto EJ Roy BM Odintsov Ag-doped manganite nanoparticlesnew materials for temperature-controlled medical hyperthermia J BiomedMater Res A 91 (2009) 1048ndash1055
[124] NK Prasad L Hardel E Duguet D Bahadur Magnetic hyperthermia withbiphasic gelof La1minus xSr xMnO3 and maghemite J Magn Magn Mater 321 (2009)1490ndash1492
[125] NK Prasad K Rathinasamy D Panda D Bahadur TC tuned biocompatiblesuspension of La073Sr027MnO3 for magnetic hyperthermia J Biomed MaterRes B Appl Biomater 85 B (2008) 409ndash416
[126] HS Panda R Srivastava D Bahadur In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids JPhys Chem B 113 (2009) 15090ndash15100
[127] D Pan H Zhang T Zhang X Duan A novel organicndashinorganic microhybridscontaining anticancer agent doxi1047298uridine and layered double hydroxidesstructure and controlled release properties Chem Engn Sci 65 (2010)3762ndash3771
[128] L Qin M Xue W Wang R Zhu S Wang J Sun R Zhang X Sun The in vitro and
in vivo anti-tumor effect of layered double hydroxides nanoparticles as deliveryfor podophyllotoxin Inter J Pharma 388 (2010) 223ndash230
[129] H Nakayama K Kuwano M Tsuhako Controlled release of drug fromcyclodextrin-intercalated layered double hydroxide J Phys Chem Solids 69(2008) 1552ndash1555
[130] YH Xue R Zhang XY Sun SL Wang The construction and characterization of layered double hydroxides as delivery vehicles for podophyllotoxins J MaterSci Mater Med 19 (2008) 1197ndash1202
[131] L Dong Y LiW-G Hou S-JLiu Synthesisand release behavior of composites of camptothecin and layered double hydroxide J Sol State Chem 183 (2010)1811ndash1816
[132] S-J Ryu HJungJ-MOh J-K Lee J-H Choy Layered doublehydroxide as novelantibacterial drug delivery system J Phys Chem Solids 71 (2010) 685ndash688
[133] HS Panda R Srivastava D Bahadur Intercalation of hexacyanoferrate(III) ionsin layered doublehydroxides a novel precursor to formferri-antiferromagneticexchange coupled oxides and monodisperse nanograin spinel ferrites J PhysChem C 113 (2009) 9560ndash9567
[134] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy anddiagnosis Adv Drug Deliv Rev 54 (2002) 631ndash651
[135] B Stella S Arpicco MT Peracchia D Desmaeumlle J Hoebeke M Renoir JDAngelo L Cattel P Couvreur Design of folic acid-conjugated nanoparticles fordrug targeting J Pharm Sci 89 (2000) 1452ndash1464
[136] IJ Majoros A Mayc T Thomas CB Mehta JR Baker PAMAM dendrimer basedmultifunctional conjugates for cancer therapy synthesis characterization and
functionality Biomacromology 7 (2006) 572ndash
579[137] EC Ramsay SN Dos WH Dragowsk JJ Laskin MB Bally The formulation of lipid based nanotechnologies for the delivery of 1047297xed dose anticancer drugcombinations Curr Drug Del 2 (2005) 341ndash351
[138] TC Yih M Al Fandi Engineered nanoparticles as precise drug delivery systems J Cell Biochem 97 (2006) 1184ndash1190
[139] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
[140] M Johannsen B Thiesen P Wust A Jordan Magnetic nanoparticle hyperther-mia for prostate cancer Int J Hyperthermia 26 (2010) 790ndash795
[141] M Johannsen U Gneveckow K TaymoorianB ThiesenN WaldoumlfnerR ScholzK Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315ndash323
[142] B Thiesen A Jordan Clinical applications of magnetic nanoparticles forhyperthermia Int J Hyperthermia 24 (2008) 467ndash474
[143] M Johannsen U Gneveckow K Taymoorian B Thiesen N Waldoumlfner R Scholz K Jung A Jordan P Wust SA Loening Morbidity and quality of life duringthermotherapy using magnetic nanoparticles in locally recurrent prostate cancerresults of a prospective phase I trial Int J Hyperthermia 23 (2007) 315 ndash323
[144] FKH van Landeghem K Maier-Hauff A Jordan K-T Hoffmann U Gneveck-owc R Scholz B Thiesen W Bruumlck A von Deimling Post-mortem studies inglioblastoma patients treated with thermotherapy using magnetic nanoparti-cles Biomaterials 30 (2009) 52ndash57
[145] KM Hauff R Rothe R Scholz U Gneveckow P Wust B Thiesen A Feussner Avon Deimling N Waldoefner R Felix A Jordan Intracranial thermotherapyusing magnetic nanoparticles combined with external beam radiotherapyresults of a feasibility study on patients with glioblastoma multiforme JNeurooncol 81 (2007) 53ndash60
1281S Chandra et al Advanced Drug Delivery Reviews 63 (2011) 1267 ndash1281