Review Article Applications of Thermoresponsive Magnetic ...downloads.hindawi.com/journals/jnm/2015/350596.pdf · moresponsive magnetic particles [ ]. e refore, we envis-aged that

Review ArticleApplications of Thermoresponsive Magnetic Nanoparticles

Ibrahim Yildiz1 and Banu Sizirici Yildiz2

1Applied Mathematics amp Sciences Department Khalifa University PO Box 127788 Abu Dhabi UAE2Department of Civil Infrastructure and Environmental Engineering Khalifa University PO Box 127788 Abu Dhabi UAE

Correspondence should be addressed to Ibrahim Yildiz ibrahimyildizkustaracae

Received 2 June 2015 Accepted 15 October 2015

Academic Editor Nguyen V Long

Copyright copy 2015 I Yildiz and B Sizirici YildizThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

In recent years magnetic nanoparticles carrying thermoresponsive polymeric coatings have gained increasing attention inmaterialsciences due to the fact that resultant platforms offer controllable modalities such as imaging drug delivery and magneticseparation As a result novel materials including biosensors therapeutic platforms imaging agents and magnetic separators havebeen realized Since the number of publications reporting the applications of thermoresponsivemagnetic nanoparticle has increasedsteadily over the years a comprehensive review will be beneficial In this paper we aim to review publications studying applicationsof thermoresponsive nanoparticles in biomedical sciences as well as in environmental and chemical sciencesThe paper also brieflydiscusses chemical formulations characterizations and properties of the thermoresponsive magnetic particles and then providesfuture outlooks

1 Introduction

Thermoresponsive polymers have the ability to change theirconformational states based on a variable temperature inputin solution and this phenomenon has been utilized to designa variety of smartmaterials in various fields [1ndash9]Most of thethermoresponsive polymers display a phase transition froman extendedhydrophilic coil to a globularhydrophobic stateupon heating above a certain temperature known as lowercritical solution temperature (LCST) [10] Polymers of thistype exhibit a soluble state in water below their LCST asa result of considerable hydrogen bonding with surround-ing water molecules By contrast above their LCST inter-and intramolecular hydrogen bonding dominates betweenpolymer chains Besides intramolecular hydrophobic inter-actions also become prominent above their LCST thereforea globularshrunken less water soluble state is producedIn fact it is this feature that makes LCST-type polymersattractive as smart tools in material and biomedical sciencesBased on a variable temperature input shrinkingswellingor aggregationdispersion of polymer units leads to con-trollable microscopic or macroscopic changes [11] Poly(N-isopropylacrylamide) (PNIPAAm) is a well-studied ther-moresponsive polymer since its LCST is close to the physi-ological temperature and was utilized mostly in biomedical

applications [12] Another interesting aspect of PNIPAMis that its LCST can be modified using hydrophilic orhydrophilic comonomers and copolymers displaying higheror lower LCST could be synthesized [13] In addition to PNI-PAAm there are a number of other polymers showing LCST-type behaviors such as poly(N-vinylcaprolactam) (PNVCL)poly(oligo(ethylene glycol)-methacrylate) (POEGMA) andpoly(N-dimethylacrylamide) (PDMAAm) and readers maybe referred to the comprehensive reviews for the detailed listsof (co)polymers and their properties [11 14 15] Alternativelya different type of thermoresponsive polymers albeit notas common as the LCST-type is known as upper criticalsolution temperature (UCST) polymers and they display areversible phase change from less soluble tomore soluble stateupon heating above their UCST [16]

Controlledliving radical polymerization (CLRP) tech-niques such as reversible-addition fragmentation chain trans-fer (RAFT) polymerization [17] atom transfer radical poly-merization (ATRP) [18] and nitroxide-mediated polymeriza-tion (NMP) [19] had an immense impact on the generation ofnovel thermoresponsive polymers Due to the fact that LCSTof polymers depends mostly on polymer structure compo-sition and end functionality these techniques have pavedways to the generation of thermoresponsive polymers that

Hindawi Publishing CorporationJournal of NanomaterialsVolume 2015 Article ID 350596 12 pageshttpdxdoiorg1011552015350596

2 Journal of Nanomaterials

have tunable LCSTs and properties Furthermore the devel-opment of novel orthogonal chemistries [20] to functionalizepolymers with other molecules drugs imaging moietiesand targeting groups or to functionalize nanoparticles withpolymers has brought about new designs and formulationsof composite nanomaterials having multistimuli responsivebehaviors and multimodal features [2]

In this review we surveyed publications focusing onthe design and construction of hybrid composite mate-rials composed of thermoresponsive polymeric shells andmagnetic core particles However the emphasis was givento the application-based studies For the detailed syntheticprocedures and characterizations readers may be referred tothe publications focusing exclusively on material design andengineering rather than applications [21ndash27] Although mostof the publications inherently tend to align with biomedicalapplications [28] new studies have started to appear inenvironmental and chemical sciences such as water treatment[29] and catalysis [30] In 2009 Liu et al have publisheda review article with the biomedical emphasis in this field[31] Similarly Medeiros et al have published a review articlein 2010 covering all types of stimuli responsive magneticparticles in biomedical sciences with little emphasis on ther-moresponsive magnetic particles [32] Therefore we envis-aged that a comprehensive recent review on the applicationsof thermoresponsive magnetic nanoparticles in material andbiomedical sciences will be beneficial to researchers havinginterests in this field

2 Thermoresponsive Magnetic Nanoparticles

Magnetic nanoparticles (MNPs) in particular Fe3O4and

120574-Fe2O3 are heavily utilized platforms in various research

areas especially in biomedical sciences due to their appar-ent biocompatibility and unique size-dependent properties[33] MNPs were widely employed as drug carriers [34]Magnetic Resonance Imaging (MRI) contrast agents [35]hypothermic therapeutics [36] and magnetic separators forcells [37] and biomolecules [38] Integration of MNPs andthermoresponsive polymers into a compositehybrid core-shell system results in multistimuli responsive platformsTherefore manipulation of two external stimuli namelythe temperature and the magnetic field may lead to thedesign of smart devices capable of being turned ldquoONrdquo orldquoOFFrdquo at convenience In the following subsections specificapplications of the hybridMNPsthermoresponsive polymerswill be covered

21 Drug Delivery and Imaging Thermoresponsive polymersin drug delivery applications provide controlled release oftherapeutics with the temperature stimulus Drug loadedpolymers exhibit decreases in their volumes above theirLCST as a result of a phase change from extended coil toglobular form which causes the diffusion of entrapped drugmolecules from polymer particles into the surrounding envi-ronment [11] Incorporation of MNPs into these constructsin essence might provide additional benefits (i) Magneticcore component could be used as an internal heat source as aresult of magnetically induced heating and this could trigger

shrinking of polymer shell [31] (ii) preferential accumulationof the polymers into the targeted locations could be achievedby utilizing magnetic force and this process is known asMagnetic Drug Targeting (MDT) [53] (iii) MRI could bebenefitted for imaging and diagnostic applications [54]

In this regard Purushotham et al have reported formula-tion of a thermoresponsive drug delivery system based on 120574-Fe2O3MNPs [55] PNIPAAm has been coated on the surface

of MNPs by means of dispersion free-radical polymerizationof NIPAM monomers Common therapeutics doxorubicinwas loaded into the polymeric shell (Figure 1) The drugrelease profile of resultant system was tested in vitro undermagnetically induced heating conditions and therapeuticallysignificant amount of drug release was observed Howeverthermally induced drug delivery process has proven to beinefficient Furthermore in vivo MDT was studied usingbuffalo rat model which was implanted with hepatocellularcarcinoma cells in liver After the implantation and thegrowth of the tumor drug loaded particles were injectedthrough the main hepatic artery of the rat model followedby placement of a permanent magnet over the liver forsome period MRI and histology studies have shown efficientlocalization of the particles in the tumoral region and theliver

In another study Kim et al have prepared a magneticplatform composed of poly(N-isopropylacrylamide-co-acrylamide)-block-poly(120576-caprolactone) (P(NIPAAm-co-AAm)-b-PCL) and superparamagnetic iron oxide nano-particles particles (SPIONs) [56] Amphiphilic nature ofthe copolymer favored formation of polymeric micellarstructures in aqueous solution and it was found thatdoxorubicin molecules were encapsulated efficiently bymicelles In vitro drug release profile has been testedthrough alternating the temperature between physiologicaltemperature and LCST (43∘C) of the polymer and it wasshown that the rate of drug release was significant atand above LCST Interestingly amount of the releaseddrugs was significantly higher at LCST with magneticallyinduced heating This phenomenon was attributed to theefficient heat transfer to the polymeric shell from nearbySPIONs while thermal heating of the polymer shell requiredmultistep heat transfer from the surrounding matrix Toassess the applicability of the construct in in vitro cell studiesmagnetic micelles were functionalized with an integrin 1205734antibody which is specific to A9 antigen overexpressed inthe squamous cell carcinoma of the head and neck Theexperiments revealed that magnetic micelles were localizedon the surface of the squamous cells whereas magneticmicelles without the antibody did not interact with thecells However no further studies were reported in terms ofthermally or magnetically induced drug delivery

Hoare et al have formulated a membrane-baseddrug delivery platform composed of ethyl cellulosemembrane matrix SPIONs and a thermoresponsive nanogelwhich was produced by copolymerization of NIPAMN-isopropylmethacrylamide (NIPMAAm) acrylamide(AAm) and NN-methylenebisacrylamide cross-linker [57](Figure 2) LCST of the copolymer was controlled byvarying the monomer ratios With the adjustment of LCST

Journal of Nanomaterials 3

DehydrationvacuumT lt LCST

T lt LCST


T lt LCST

T gt LCST

Aqueousmedia

(ii) Slower releaseSwollen matrix

(i) Faster releaseDehydrated matrixDox loaded

dehydrated matrix

Dox loadingaqueous soln

Dox loaded swollenPNIPAM matrix

PNIPAMcoating

PNIPAM matrixMNP cluster

(a)

(b) (c)

Figure 1 Formulation of thermoresponsiveMNP for drug delivery applications (a)NIPAMmonomers togetherwith a cross-linkermonomerwere polymerized around clusters of 120574-Fe

2O3MNPs to generate thermoresponsive MNPs Dehydration of the particles below LCST under

vacuum led to shrinking of the composite system (b) Loading of a cancer chemotherapeutics doxorubicin in aqueous solution is governedthroughhydrophobic interaction of drugmoleculeswith the polymeric shell (c) In vitrodrug release could be achieved setting the temperatureabove LCST and accompanying phase change fromcoil to globule causes expulsion of drugmolecules into the surroundingmedium (reprintedwith the permission of publisher IOP Publishing Ltd copyright 2009 from [55])

membrane thickness and gel loading it was demonstratedthat the flux of a model drug from a reservoir across themembrane could be increased manifold upon application ofan external magnetic field It was shown that the flux couldbe turned ON and OFF by switching on and off the magneticfield and a range of drugs with molecular weight from500Da to 40 kDa could be transported across the membraneAlthough the systemwas thoroughly characterized and testedand it produced very promising results on a model systemits in vivo applicability and biocompatibility need to be testedand engineered for potential biomedical applications

Hiraiwa et al have investigated the feasibility of employ-ing commercially available thermoresponsive MNPs as MRIcontrast agents to map sentinel lymph node (SLN) bysubcutaneous injection of these particles into the thoracicwall of model rats [58] They have tested magnetic particleshaving different PNIPAAm loadings such asTherma-Max 36with the LCST of 36∘C Therma-Max 42 with the LCST of42∘C Therma-Max 55 with the LCST of 55∘C and a controlFerridex without thermoresponsive polymer coating They

hypothesized that formulations with proper LCSTs will beable to enter the lymphatic vessels after injection and due tophysiological temperature these particles will aggregate andwill be retained in SLN Post-MRI and histological studiesshowed that Therma-Max 36 aggregated just after injectionand was not able to enter SLN whereas Therma-Max 42Therma-Max 55 and Ferridex were able to enter into SLNFurthermore Therma-Max 42 aggregated in SLN howeverTherma-Max 55 and Ferridex were carried to distant lymphnodes (DLN) These results clearly indicated that thermore-sponsive MNPs have great potentials as being superior MRIcontrast agents

Wadajkar et al have developed a magnetic platform witha thermoresponsive polymeric surface for MRI applications[59] A silica shell was grown on the commercially avail-able iron oxide nanoparticles followed by the attachmentof vinyl groups Poly(N-isopropylacrylamide-co-acrylamide-co-allylamine) (P(NIPAAm-co-AAm-co-AH)) was graftedon the surface of particles throughpolymerization of the vinylgroups with the corresponding monomers The polymeric


20nm

(a)

2120583m

(b)

~1 cm

(c)

Weak drug release Strong drug release

Nanogel

High conc drugDrugreservoir

Exteriorspace

Hydrophobicmatrix

Magneticnanoparticle

(d)

Figure 2 Fabrication of a drug deliverymembrane based on nanocomposite materials composed of SPIONs and thermoresponsive hydrogel(a) TEM micrograph and diffraction pattern of SPIONs synthesized from alkaline hydrolysis of iron salts (b) TEM micrograph of hydrogelsynthesized via copolymerization of NIPAAm NIPMAAm and AAm (c) Photograph of the composite membrane prepared throughdissolving SPIONs ethyl cellulose and hydrogel in ethanol followed by evaporation to form a thin film (d) Membrane flux assay wasperformed by placing membrane film between two glass flow chambers filled with saline A fluorescent model drug was placed in one of thechambers and upon the temperature or magnetic field stimuli drug molecules were transported into the other chamber across the membranedue to increased permeability of the membrane as a result of shrinking of hydrogel (reprinted with the permission of publisher AmericanChemical Society copyright 2011 from [57])

surface was chemically modified with the prostate cancerspecific R11 peptides In vitro cell culture studies usingprostate cancer cell lines showed the localization of particlesinside the cells In vivo animal studies have revealed thatsystemically injected formulation containing R11 targetingpeptide has accumulated more in the tumor as comparedto the control animals injected with the same formulationwithoutR11 peptide Besides the accumulation of the targetedformulation in the tumor has led to a significant T2 signalintensity decrease whereas the decrease with the nontargetedformulation was negligible Therefore this platform haspotentials in the diagnosis of the prostate cancer using MRItechnique Although no studies regarding the thermore-sponsive behaviour of the polymer coating was mentionedpossible drug delivery and hypothermia studies deserve to beexplored in future studies

Thermoresponsive MNPs could be exploited more in thefuture studies as both contrast agents and targeted drugdelivery vehicles using MDT technique To this end morestudies are needed to design and engineer formulations thatare biocompatible safe and easy to manufacture In Table 1a variety of drug delivery systems and MRI contrast agentsbased on MNPs and thermoresponsive polymers have beensummarized [39ndash45]

22 Magnetic Separation Purification and isolation of pep-tides cells and biomolecules including proteins nucleicacids enzymes and antibodies rely on the chromatographicand electrophoretic techniques which in general requirelengthy time of procedures and involve multiple steps [60ndash62] Most of these techniques invoke interaction of anaffinity ligand antibodies peptides and synthetic molecules


Table 1 Thermoresponsive polymer-magnetic nanoparticle composites for drug delivery and imaging application

Magnetic core-size(diameter-TEM) Polymer LCST Application Reference

Mn1minus119909

Zn119909Fe2O4-50 nm

Poly(NN1015840-isopropylacrylamide-co-N-hydroxymethylacrylamide)(P(NIPAAm-co-HMAAm))

40∘C In vitro hyperthermia [39]

Fe3O4-Au-115 nm PNIPAAm 32∘C Surface plasmon resonance

(SPR) based heating [40]

Fe3O4-8 nm

Dextran grafted poly(N-isopropylacrylamide-co-NN-dimethylacrylamide)[dextran-g-poly(NIPAAm-co-DMAAm)]

38∘C Not reported [41]

Fe3O4-12 nm PNIPAAm 40∘C In vitro drug delivery magnetic

heating [42]

120574-Fe2O3-75 nm Poly(vinyl alcohol)-b-poly(N-vinylcaprolactam)

(PVOH-b-PNVCL) 41∘C In vitro drug delivery magneticheating [43]

Fe3O4-13 nm Poly(NN1015840-isopropylacrylamide-co-styrene)

(P(NIPAAm-co-St)) 27ndash35∘C In vivoMRI [44]

Fe3O4-SiO2-80 nm Poly(NN1015840-isopropylacrylamide)-block-polystyrene

(PNIPAAm-b-PSt) 32∘C In vitroMRI [45]

which is generally immobilized on a solid matrix withthe biomolecule of interest [63] Magnetic separation uti-lizing MNPs functionalized with the affinity ligands haveemerged as a complementaryalternative technique to thechromatography techniques [38] In magnetic separationbiomolecules in complex mixtures could be separated andisolated in a single step and in a relatively short period of timeAn ideal magnetic separation platform should have a highmagnetophoretic mobility that is to say it should respondto external magnetic field fast and this property dependson the size and magnetic susceptibility of the materials[64] Both commercial and home-made micrometer sizemagnetic particles were extensively used in the separationof the biomolecules due to the fast magnetic responses [65]Although small size MNPs tend to respond poorly to lowmagnetic field gradients they offer a variety of inherentadvantages as compared to micron size counterparts suchas high binding capacity and faster binding kinetics [66]So as to harness the potentials of the small size MNPs aseffective magnetic separators several strategies have beendeveloped to increase magnetic response including aggre-gating particles confining particles within polymers andencapsulating particles in silica matrix [67] However thesestrategies result in loss of high surface to volume ratioRecently there have been efforts to develop strategies toinduce reversible aggregationdispersion of small MNPs sothat higher magnetic responses could be maintained withoutsacrificing high surface to volume ratio [68 69] To thisend surface modification of MNPs with thermoresponsivepolymers is one of the most promising alternatives Inprinciple below LCST of the polymers MNPs modified withaffinity ligands could bind to the biomolecules and thenabove LCST magnetic separation could be performed moreeffectively

In this regard Nash et al have developed a novel systemto separate amodel protein streptavidin fromhumanplasmausing PNIPAAm and PNIPAAm functionalized Au and

Fe3O4nanoparticles [70] (Figure 3) Negatively charged Au

nanoparticles were modified with positively charged PNI-PAAm carrying an affinity ligand biotin against strepta-vidin using electrostatic charge interaction whereas Fe

3O4

nanoparticles were directly prepared in the presence ofPNIPAAm as a stabilizer ligand In this setup incubationof PNIPAAm Au-PNIPAAm-biotin and Fe

3O4-PNIPAAm

with streptavidin spiked plasma at 45∘C (above LCST) causedaggregation of particles together with streptavidin By meansof magnetic separation and redispersion Au-PNIPAAm-biotin bound streptavidin was concentrated manifolds intoa smaller volume and was quantified without any furthertreatment with a lateral flow immunochromatography test

Lai et al have designed a microfluidic separation systembased on PNIPAAm having hydrophobic alkyl chain at oneterminus and polar carboxylic acid at the other terminus[71] PNIPAAm was used as a micellar template and sur-factant to synthesize 120574-Fe

2O3MNPs The surface carboxylic

acid moieties were chemically modified with biotin ligandsWith the manipulation of both the magnetic field and thetemperature it was shown that streptavidin bound MNPscould be accumulated on the walls of a microfluidic channelIn this way a target biomolecule could be captured ina heterogeneous mixture below LCST and then could beselectively accumulated in the microfluidic device by bothraising the temperature above LCST and applying magneticfield By either decreasing the temperature below LCST orturning off the magnetic field MNPs bound with proteinscould be recovered

Hoshino et al have designed a novel method to separateneutrophils short lived immune cells against microorgan-isms from macrophages by utilizing commercial thermore-sponsive MNPs modified with streptavidin (Therma-MaxLSA Streptavidin Magnabeat Incorporated Chiba Japan)[72] The magnetic construct has shown an average diameterof 1676 nm at 10∘C (below LCST) and aggregated to a biggersize at 40∘C (above LCST) according to DLS measurements


Biotinylated polymer

Mixed AuNPmNP aggregate

Antistreptavidin IgG

Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield

Discard supernatant andredissolve into smallervolume of buffer below

LCST

Detection by lateralflow immunoassay

ldquoCleaned uprdquo and concentratedparticle mixture

bb

b b

b b

bb

bb

b

bb

b

bb

b b

Figure 3 Separation and enrichment of a model protein using thermoresponsive MNPs and Au nanoparticles Au nanoparticlesfunctionalized with a thermoresponsive block polymer PNIPAAm-b-P DMAEAm were conjugated to biotin molecules to capturestreptavidin from spiked human plasma Capture of streptavidin was carried out by incubation of the plasma with PNIPAAm-b-PDMAEAm-Au PNIPAAm-MNP and free PNIPAAm followed by magnetic separation above LCST (45∘C) After removing supernatant the sample wasdissolved in buffer below LCST which caused dispersion of assembly and streptavidin was still bound to Au nanoparticles The sample wasdirectly applied to lateral flow assay which contained anti-streptavidin antibody for detection of streptavidin (reprinted with the permissionof publisher American Chemical Society copyright 2010 from [70])

A biotinylated macrophage-specific anti-F480 antibody hasbeen functionalized on the surface of the MNPs through thestreptavidin-biotin interaction Incubation of the resultantMNPs with the Murine peritoneal fluid containing neu-trophils andmacrophages below LCST has led to the captureof macrophages Aggregates consisting of MNPs bound withthe macrophages were obtained above LCST and separatedwith a permanent magnet leaving behind peritoneal fluidcontaining mostly neutrophils This was validated throughfluorescence-activated cell sorting (FACS) study

It is obvious that thermoresponsive MNPs will be stud-ied in great detail for biomedical separation purposes infuture and it seems that there should be more emphasison the isolation or recovery of biomolecules from MNPsTo this end a number of strategies could be adapted fromchromatographic separation techniques to elute biomoleculesfrom MNPs Table 2 summarizes a variety of magneticseparation platforms in biomedical field based on MNPs andthermoresponsive polymers [46ndash52]

23 Environmental Applications Thermoresponsive MNPshave proved to be a promising tool in environmental sciencesespecially in water treatment and desalination applicationsIn this regard Zhao et al have designed a forward osmosis(FO) draw solution based on Fe

3O4nanoparticles encapsu-

lated within a thermoresponsive copolymer poly(sodiumstyrene-4-sulfonate-co-N-isopropylacrylamide) (P(SSS-co-NIPAAm)) through ligand exchange process [73] In thisdesign they tested the ability of draw solution to drawthe sea water through FO membrane and the resultingosmotic pressure and the water fluxes were measured Thepolyelectrolyte PSSS has provided the driving force for theflux which was caused by higher osmotic pressure of PSSSthan the seawater In a typical setup (Figure 4) water wasdrawn across the membrane towards the draw solution andthen the draw solution was subjected to magnetic separationabove LCST and this process produced regenerated drawsolute and fresh water


Table 2 Thermoresponsive polymer-magnetic nanoparticle composites for magnetic separations of biomolecules and cells

Magnetic core-size(diameter) Polymeranalyte LCST Affinity ligandapplication Referencenote

Fe3O4polystyrene-

(Therma-Max) 100 nmPINAAmthyroid stimulating hormone(TSH) 22∘C

120573-antibodyTSH isolationand detection(Immunoassay)

[46]

Fe3O4-SiO2-80 nm

Poly(2-(2-methoxyethoxy)ethylmethacrylate-co-methacrylicacid-co-N-(4-vinyl)-benzyl iminodiaceticacid) P(MEO

2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C

Molecularly imprintedlysosome receptorthermalcapture and release oflysosome

[47]

120574-Fe2O3-SiO2-5 120583m Poly(N-vinylcaprolactam) (PNVCL)Bovine

Serum Albumin (BSA) 334∘CHydrophobicinteractionproteinseparation-purification

[48]size measurementwas based on SEM ofwhole assembly

Fe3O4-100 nm

Poly(polyethyleneglycol-co-N-isopropylacrylamide)poly(PEG-co-PINAAm)lysozyme

40∘CHydrophobicinteractionproteinseparation-purification

[49]size measurementbased on TEM ofaggregates due toinclusion complexesbetween cyclodextrinand PEG

PLGA-iron oxide MNPs-(Meliorum technologiesRochester NY) silicamicroparticles-50ndash100120583m

Poly(N-isopropylacrylamide-co-allylamine)poly(NIPAAm-co-AH)stem cells 33∘C

CD34 antibodiesisolationenrichment anddetachment of endothelialprogenitor cells (EPCs)


Fe3O4-100 nm

Poly(NN1015840-isopropylacrylamide-co-N-methacroyl-N1015840-biotinylpropylenediamine)(P(NIPAAm-co-MBPDA))ZZ-displayingyeast cells

30∘C

Anti-goat IgG (heavy andlight chains) (rabbitIgG)affinity selection andseparation of target cellsfrom model yeast cells

[51]size measurementwas based on DLS ofwhole assembly

Fe3O4ndashdextran-

(Therma-Max) 70 nm

Poly(N-acryloyl glycinamide-co-N-(3-biotinamidepropyl)-methacrylamide)P(NAGAM-co-NBPMA)

18∘C(UCST)

(i) CD4 antibodycaptureand enrichment ofArabidopsis protoplasts(plant cells)(ii) Silkworm storageprotein (SP2)anti-SP2antibody


In a similar fashion Razmjou et al have designeda FO system based on a draw solution composed of120574-Fe2O3

nanoparticle and poly(sodium acrylate-co-N-isopropylacrylamide) (P(SA-co-NIPAAm)) hydrogel [74]The polymer was synthesized in the presence of MNPs andthis process yielded MNPs physically trapped within thepolymeric units They have studied the swelling behavior ofthe draw solution the water flux through FOmembrane andwater recovery was assessed through both thermal heatingandmagnetic heating It was found that the recovery of waterwas higher with magnetically induced heating as comparedto thermal heating and it was attributed to the efficientlocal heating of hydrogels through magnetic particles whichresulted in an efficient phase change of the polymers

Oil harvesting from industrial wastewater and spill acci-dent sites is another potential application for thermorespon-sive MNPs Chen et al have developed an oil harvestingplatform consisting of Fe

3O4ndashSiO2microsphere core and

PNIPAAm polymer shell [75] Polymeric layer was grownusing ATRP technique The amphiphilic PNIPAAm shellinteracted with the oil droplets in water through hydrophobic

interactions and as a result bigger oily emulsions could beseparated from water with an external magnet Upon settingthe temperature above LCST oil could be released from theparticles as a result of destabilization of the emulsion causedby phase transition of the polymer

Thermoresponsive MNPs showed very promising resultsin desalination of seawater In the future there will be a grow-ing demand to produce fresh water from the seawater To thisend more studies are needed to integrate thermoresponsiveMNPs into the current membrane technologies

24 ChemicalBiological Catalysis Over the last decadeMNPs have been incorporated into various platforms in orderto carry out chemical and biological transformations either asreactants or as catalysts [30] Inclusion of thermoresponsivepolymers into these types of constructs in essence couldprovide a couple of benefits Recovery of the catalyst boundto magnetic platform could be achieved through magneticseparation with the modulation of aggregationdispersion ofthe thermoresponsive unit with a variable temperature inputBesides kinetics of the catalytic reactions could be controlled


SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs

Regenerateddraw solution

Draw solutionreservoir

Brine water Diluteddraw solution

Drawsolution

Seawater

Heater

Figure 4 Application of thermoresponsive MNPs as FO draw solute in water desalination The polyelectrolyte present in thethermoresponsive polymer creates an osmotic pressurewhich leads to the flux ofwater from seawater through themembrane towards the drawsolution Setting temperature above LCST leads to shrinking of the polymer and dehydration of the draw solute and thermoresponsiveMNPscould be separated and regenerated with the application of magnetic field (reproduced with permission of publisher American ChemicalSociety copyright 2013 from [73])

via control of the size of MNPs with aggregationdispersionprocess Furthermore surfaces of the MNPs could provide ananoreactorcontainer for the catalytic transformations

Crassous et al have formulated a platform composedof respectively 120574-Fe

2O3magnetic core a silica layer and

poly(N-isopropylmethacrylamide) (PNIPMAAm) shell [76]The polymer layer was grafted using surfactant free seedprecipitation polymerization Small Au nanoparticles weresynthesized inside the polymeric shell as the catalysis com-ponent A different thermoresponsive polymer (PNIPAAm)layer was grown as the outermost polymeric shellThe secondlayer of thermoresponsive polymer PNIPAAm has grownso as to modulate the catalytic activity of Au particles andto provide better colloidal stability to overall compositematerial The catalytic activity of the platform before andafter the growth of second polymer shell was tested usingreduction of 4-nitrophenol to 4-aminophenol by NaBH

4and

following with UV-Vis spectrophotometry It was found thatthe rate of reaction without second shell is purely thermallycontrolled However for the composite system having thesecond polymer shell the rate dependence is controlled byboth thermal and the phase transition of PNIPAAm It wasalso shown that the catalyst could be removed and recycledutilizingmagnetic separation Even though it proved that it isan efficient catalytic platform the formulation of the systemis complex and requires laborious work-ups

Liu et al have formulated a similar catalytic system com-posed of Fe

3O4magnetic core poly(N-isopropylacrylamide-

co-2-(dimethylamino)ethyl methacrylate) (P(NIPAAm-co-DMAEMA)) thermoresponsive shell and Au nanoparticles[77] Incorporation of the Au particles into final constructwas driven by electrostatic interaction of the positivelycharged polymer and the negatively charged Au particlesThe catalytic activity of systemwasmeasured using reductionof 4-nitrophenol and it was found that the rate of catalysisdecreased as the temperature was increased above LCST Itwas concluded that thermally activated phase change led tothe aggregation of Au particles thus less surface area wasavailable for the catalytic reduction Furthermore the catalystwas separated with a magnet providing recycling option

Biocatalysis utilizes enzymes to produce chemicals thatare essential for both medical applications and industrialpurposes [78] It provides a number of advantages over thetraditional wet-lab synthesis of the chemicals Furthermorethe reuse of catalyst especially expensive enzymes bearsutmost importance due to cost and availability factorsEmployment of thermoresponsive MNPs in this field inessence could be an efficient solution to the reusabilityissues Marten et al have prepared a biocatalyst platformconsisting of Fe

3O4core particles surrounded by thermore-

sponsive polymers synthesized through ATRP techniqueusingmonomers of oligo ethylene glycol basedmethacrylates


[79] As the catalytic component porcine pancreas trypsinwas conjugated to the platform The activity of immobilizedcatalyst was tested using benzoyl-Arg p-nitroanilide whichhydrolyzes to p-nitroaniline and could be traced with UV-Vis spectroscopy It was found that above LCST of thepolymer the rate of reaction increased due to the shrinkingof polymer layer which exposed the enzyme to the substrateto a considerable extent Furthermore it was shown thatmagnetically induced heating caused phase transition of thepolymer faster than thermal heating

Although the use of thermoresponsiveMNPs has tremen-dous potentials in the biocatalysis field the number ofstudies is limited Potential future studies might focus on thedevelopment of conjugation protocols that yield the immo-bilization of enzymes on the surface of thermoresponsiveMNPs in optimum quantity and without loss of catalyticactivity

25 Miscellaneous Applications In addition to the previouslydescribed four categories there are some studies relatedwith thermoresponsive MNPs which cannot be placed inany category Although they belong mostly to biomedicalapplications it is worth mentioning some of these studies ina separate subheading Thermoresponsive MNPs were usedin the fabrication of 3D cell support matrices to grow stemcells [80] in cellular labeling and in vivo cellular tracking[81] in temperature sensing of living cells [82] and in sensinginorganic ions such as arsenic and cadmium [83]

3 Conclusion and Future Outlook

So far it has been validated through extensive research thatcombining multiple materials into a single platform haspotentials to generate multistimuli responsive smart devicesthat could be employed in many fields ThermoresponsiveMNPs may indeed find more application fields with thehelp of collaboration of chemical material and engineeringsciences due to the interdisciplinary nature of applications Itis expected that these materials will be components of assaysimaging agents therapeutics sensors and multifunctionaldevices and it is not hard to visualize that they will beintegral parts of many routine lab testing in medicine aswell as nanoreactors in chemical sciences Future studiesmight be directed to study alternative ways of linking ther-moresponsive polymer with MNPs Most of the reportedprotocols as outlined in the previous sections rely on thepolymerization of corresponding monomers on the surfaceof MNPs However preformed polymeric architectures withreactive groups could be immobilized on the surface ofMNPs using effective covalent chemistries UCST polymershave been underutilized in the applications so far and theymight provide flexibility in designing new platforms espe-cially in biomedical applications where temperature sensitivematerials pose technical challenges with LCST polymersIn addition to magnetic and thermoresponsive stimuli itis possible to include pH redox ion and light responsiveunits in thematerial design and thereby smart multimodulardevices and platforms could be generated

Abbreviations

LCST Lower critical solution temperaturePNIPAAm Poly(N-isopropylacrylamide)UCST Upper critical solution temperatureMNPs Magnetic nanoparticlesMRI Magnetic Resonance ImagingMDT Magnetic Drug TargetingSPIONs Superparamagnetic iron oxide

nanoparticlesDLS Dynamic light scatteringNIPMAAm N-IsopropylmethacrylamideSLN Sentinel lymph nodeFO Forward osmosis

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by the UAE National ResearchFoundationrsquos (NRF) grant UIRCA 2013-24898 and KhalifaUniversity Internal Research Fund (KUIRF) 210080

References

[1] M A Ward and T K Georgiou ldquoThermoresponsive polymersfor biomedical applicationsrdquo Polymers vol 3 no 3 pp 1215ndash1242 2011

[2] J Zhuang M R Gordon J Ventura L Li and S Thayu-manavan ldquoMulti-stimuli responsive macromolecules and theirassembliesrdquo Chemical Society Reviews vol 42 no 17 pp 7421ndash7435 2013

[3] M Joglekar and B G Trewyn ldquoPolymer-based stimuli-responsive nanosystems for biomedical applicationsrdquo Biotech-nology Journal vol 8 no 8 pp 931ndash945 2013

[4] P Bawa V Pillay Y E Choonara and L C Du Toit ldquoStimuli-responsive polymers and their applications in drug deliveryrdquoBiomedical Materials vol 4 no 2 Article ID 022001 2009

[5] E Cabane X Zhang K Langowska C G Palivan and WMeier ldquoStimuli-responsive polymers and their applications innanomedicinerdquo Biointerphases vol 7 no 9 pp 1ndash27 2012

[6] H Kanazawa and T Okano ldquoTemperature-responsive chro-matography for the separation of biomoleculesrdquo Journal ofChromatography A vol 1218 no 49 pp 8738ndash8747 2011

[7] J Zhu Y Zhang D Lu R N Zare J Ge and Z LiuldquoTemperature-responsive enzyme-polymer nanoconjugateswith enhanced catalytic activities in organic mediardquo ChemicalCommunications vol 49 no 54 pp 6090ndash6092 2013

[8] C Zhang C Li Y Chen and Y Zhang ldquoSynthesis and catalysisof Ag nanoparticles trapped into temperature-sensitive andconductive polymersrdquo Journal of Materials Science vol 49 no20 pp 6872ndash6882 2014

[9] YWang Y Kotsuchibashi Y Liu andRNarain ldquoTemperature-responsive hyperbranched amine-based polymers for solid-liquid separationrdquo Langmuir vol 30 no 9 pp 2360ndash2368 2014


[10] X Wang X Qiu and C Wu ldquoComparison of the coil-to-globule and the globule-to-coil transitions of a single poly(N-isopropylacrylamide) homopolymer chain in waterrdquo Macro-molecules vol 31 no 9 pp 2972ndash2976 1998

[11] S D Fitzpatrick L E Fitzpatrick A Thakur M A JMazumder and H Sheardown ldquoTemperature-sensitive poly-mers for drug deliveryrdquo Expert Review of Medical Devices vol9 no 4 pp 339ndash351 2012

[12] S Rimmer I Soutar and L Swanson ldquoSwitching the confor-mational behaviour of poly(N-isopropyl acrylamide)rdquo PolymerInternational vol 58 no 3 pp 273ndash278 2009

[13] K Tauer D Gau S Schulze A Volkel and R DimovaldquoThermal property changes of poly(N-isopropylacrylamide)microgel particles and block copolymersrdquo Colloid and PolymerScience vol 287 no 3 pp 299ndash312 2009

[14] D Roy W L A Brooks and B S Sumerlin ldquoNew directions inthermoresponsive polymersrdquo Chemical Society Reviews vol 42no 17 pp 7214ndash7243 2013

[15] N Shimada and A Maruyama ldquoThermoresponsive poly-mers with functional groups selected for pharmaceutical andbiomedical applicationsrdquo in Tailored Polymer Architectures forPharmaceutical and Biomedical Applications C Scholz and JKressler Eds chapter 14 pp 235ndash241 American ChemicalSociety 2013

[16] J Seuring and S Agarwal ldquoPolymers with upper critical solu-tion temperature in aqueous solution unexpected propertiesfrom known building blocksrdquo ACS Macro Letters vol 2 no 7pp 597ndash600 2013

[17] D J Keddie ldquoA guide to the synthesis of block copolymersusing reversible-addition fragmentation chain transfer (RAFT)polymerizationrdquo Chemical Society Reviews vol 43 no 2 pp496ndash505 2014

[18] K Matyjaszewski ldquoAtom transfer radical polymerization(ATRP) current status and future perspectivesrdquo Macro-molecules vol 45 no 10 pp 4015ndash4039 2012

[19] J Nicolas Y Guillaneuf C Lefay D Bertin D Gigmes andB Charleux ldquoNitroxide-mediated polymerizationrdquo Progress inPolymer Science vol 38 no 1 pp 63ndash235 2013

[20] M van Dijk D T S Rijkers R M J Liskamp C F vanNostrum and W E Hennink ldquoSynthesis and applications ofbiomedical and pharmaceutical polymers via click chemistrymethodologiesrdquo Bioconjugate Chemistry vol 20 no 11 pp2001ndash2016 2009

[21] J Zhang and R D K Misra ldquoMagnetic drug-targeting carrierencapsulated with thermosensitive smart polymer corendashshellnanoparticle carrier and drug release responserdquo Acta Biomate-rialia vol 3 no 6 pp 838ndash850 2007

[22] Y Sun X Ding Z Zheng X Cheng X Hu and Y Peng ldquoMag-netic separation of polymer hybrid iron oxide nanoparticlestriggered by temperaturerdquo Chemical Communications no 26pp 2765ndash2767 2006

[23] T GelbrichM Feyen andAM Schmidt ldquoMagnetic thermore-sponsive coreminusshell nanoparticlesrdquoMacromolecules vol 39 no9 pp 3469ndash3472 2006

[24] HWakamatsu K Yamamoto A Nakao and T Aoyagi ldquoPrepa-ration and characterization of temperature-responsive mag-netite nanoparticles conjugated with N-isopropylacrylamide-based functional copolymerrdquo Journal of Magnetism and Mag-netic Materials vol 302 no 2 pp 327ndash333 2006

[25] A M Schmidt ldquoThe synthesis of magnetic core-shell nanopar-ticles by surface-initiated ring-opening polymerization of 120576-caprolactonerdquoMacromolecular Rapid Communications vol 26no 2 pp 93ndash97 2005

[26] N V Long Y Yang T Teranishi C M Thi Y Cao andM Nogami ldquoRelated magnetic properties of CoFe

2O4cobalt

ferrite particles synthesised by the polyol method with NaBH4

and heat treatment new micro and nanoscale structuresrdquo RSCAdvances vol 5 no 70 pp 56560ndash56569 2015

[27] N V Long Y Yang T Teranishi C M Thi Y Cao and MNogami ldquoSynthesis and magnetism of hierarchical iron oxideparticlesrdquoMaterials amp Design vol 86 pp 797ndash808 2015

[28] C S Brazel ldquoMagnetothermally-responsive nanomaterialscombining magnetic nanostructures and thermally-sensitivepolymers for triggered drug releaserdquo Pharmaceutical Researchvol 26 no 3 pp 644ndash656 2009

[29] D Parasuraman A K Sarker and M J Serpe ldquoPoly(N-isopropylacrylamide)-based microgels and their assemblies fororganic-molecule removal fromwaterrdquoChemPhysChem vol 13no 10 pp 2507ndash2515 2012

[30] Q M Kainz and O Reiser ldquoPolymer- and dendrimer-coatedmagnetic nanoparticles as versatile supports for catalysts scav-engers and reagentsrdquoAccounts of Chemical Research vol 47 no2 pp 667ndash677 2014

[31] T-Y Liu S-H Hu D-M Liu S-Y Chen and I-W ChenldquoBiomedical nanoparticle carriers with combined thermal andmagnetic responsesrdquo Nano Today vol 4 no 1 pp 52ndash65 2009

[32] S F Medeiros AM Santos H Fessi and A Elaissari ldquoStimuli-responsive magnetic particles for biomedical applicationsrdquoInternational Journal of Pharmaceutics vol 403 no 1-2 pp 139ndash161 2011

[33] S Laurent D Forge M Port et al ldquoMagnetic iron oxidenanoparticles synthesis stabilization vectorization physico-chemical characterizations and biological applicationsrdquo Chem-ical Reviews vol 108 no 6 pp 2064ndash2110 2008

[34] P B Santhosh and N P Ulrih ldquoMultifunctional superpara-magnetic iron oxide nanoparticles promising tools in cancertheranosticsrdquo Cancer Letters vol 336 no 1 pp 8ndash17 2013

[35] H B Na I C Song and T Hyeon ldquoInorganic nanoparticlesfor MRI contrast agentsrdquoAdvancedMaterials vol 21 no 21 pp2133ndash2148 2009

[36] A C Silva T R Oliveira J B Mamani et al ldquoApplicationof hyperthermia induced by superparamagnetic iron oxidenanoparticles in glioma treatmentrdquo International Journal ofNanomedicine vol 6 pp 591ndash603 2011

[37] A A Neurauter M Bonyhadi E Lien et al ldquoCell isolation andexpansion using dynabeadsrdquo in Cell Separation A Kumar IGalaev and B Mattiasson Eds vol 106 of Advances in Bio-chemical EngineeringBiotechnology pp 41ndash73 Springer BerlinGermany 2007

[38] I Safarik and M Safarikova ldquoMagnetic techniques for the iso-lation and purification of proteins and peptidesrdquo BioMagneticResearch and Technology vol 2 article 7 2004

[39] C Yang R Jie L Jianbo and L Yan ldquoThermo-responsive Mn-Zn ferritepoly(NN1015840-isopropyl acrylamide-co-N- hydroxy-methylacrylamide) coreshell nanocomposites for drug-delivery systemsrdquo Journal of Biomaterials Science PolymerEdition vol 22 no 11 pp 1473ndash1486 2011

[40] P RoachD JMcGarveyM R Lees andCHoskins ldquoRemotelytriggered scaffolds for controlled release of pharmaceuticalsrdquoInternational Journal of Molecular Sciences vol 14 no 4 pp8585ndash8602 2013


[41] J L Zhang R S Srivastava and R D K Misra ldquoCoremdashshell magnetite nanoparticles surface encapsulated with smartstimuli-responsive polymer synthesis characterization andlcst of viable drug-targeting delivery systemrdquo Langmuir vol 23no 11 pp 6342ndash6351 2007

[42] M K Jaiswal M De S S Chou et al ldquoThermoresponsive mag-netic hydrogels as theranostic nanoconstructsrdquo ACS AppliedMaterials amp Interfaces vol 6 no 9 pp 6237ndash6247 2014

[43] J Liu C Detrembleur A Debuigne et al ldquoGlucose- pH- andthermo-responsive nanogels crosslinked by functional super-paramagnetic maghemite nanoparticles as innovative drugdelivery systemsrdquo Journal of Materials Chemistry B vol 2 no8 pp 1009ndash1023 2014

[44] H Zhu J Tao W Wang et al ldquoMagnetic fluorescentand thermo-responsive Fe

3O4rare earth incorporated poly(St-

NIPAM) coremdashshell colloidal nanoparticles in multimodalopticalmagnetic resonance imaging probesrdquo Biomaterials vol34 no 9 pp 2296ndash2306 2013

[45] Q Li L Zhang L Bai et al ldquoMultistimuli-responsivehybrid nanoparticles withmagnetic core and thermoresponsivefluorescence-labeled shell via surface-initiated RAFT polymer-izationrdquo Soft Matter vol 7 no 15 pp 6958ndash6966 2011

[46] H Nagaoka Y Sato X Xie et al ldquoCoupling stimuli-responsivemagnetic nanoparticles with antibodyndashantigen detection inimmunoassaysrdquo Analytical Chemistry vol 83 no 24 pp 9197ndash9200 2011

[47] N Li L Qi Y Shen J Qiao and Y Chen ldquoNovel oligo(ethyleneglycol)-based molecularly imprinted magnetic nanoparticlesfor thermally modulated capture and release of lysozymerdquo ACSApplied Materials amp Interfaces vol 6 no 19 pp 17289ndash172952014

[48] M-M Song C Branford-White H-L Nie and L-M ZhuldquoOptimization of adsorption conditions of BSA on thermosen-sitive magnetic composite particles using response surfacemethodologyrdquoColloids and Surfaces B Biointerfaces vol 84 no2 pp 477ndash483 2011

[49] L Luo H-S Zhang Y Liu et al ldquoPreparation of thermosensi-tive polymer magnetic particles and their application in proteinseparationsrdquo Journal of Colloid and Interface Science vol 435pp 99ndash104 2014

[50] A S Wadajkar S Santimano L Tang and K T NguyenldquoMagnetic-based multi-layer microparticles for endothelialprogenitor cell isolation enrichment and detachmentrdquo Bioma-terials vol 35 no 2 pp 654ndash663 2014

[51] H Furukawa R Shimojyo N Ohnishi H Fukuda and AKondo ldquoAffinity selection of target cells from cell surfacedisplayed libraries a novel procedure using thermo-responsivemagnetic nanoparticlesrdquo Applied Microbiology and Biotechnol-ogy vol 62 no 5-6 pp 478ndash483 2003

[52] N Ohnishi H Furukawa H Hideyuki et al ldquoHigh-efficiencybioaffinity separation of cells and proteins using novel ther-moresponsive biotinylated magnetic nanoparticlesrdquo NanoBio-technology vol 2 no 1-2 pp 43ndash49 2006

[53] C Alexiou R Tietze E Schreiber et al ldquoCancer therapy withdrug loaded magnetic nanoparticlesmdashmagnetic drug target-ingrdquo Journal of Magnetism and Magnetic Materials vol 323 no10 pp 1404ndash1407 2011

[54] A Arepally ldquoTargeted drug delivery under MRI guidancerdquoJournal of Magnetic Resonance Imaging vol 27 no 2 pp 292ndash298 2008

[55] S Purushotham P E J Chang H Rumpel et al ldquoTher-moresponsive coremdashshellmagnetic nanoparticles for combined

modalities of cancer therapyrdquo Nanotechnology vol 20 no 30Article ID 305101 2009

[56] D-H Kim E A Vitol J Liu et al ldquoStimuli-responsive mag-netic nanomicelles as multifunctional heat and cargo deliveryvehiclesrdquo Langmuir vol 29 no 24 pp 7425ndash7432 2013

[57] T Hoare B P Timko J Santamaria et al ldquoMagneticallytriggered nanocomposite membranes a versatile platform fortriggered drug releaserdquo Nano Letters vol 11 no 3 pp 1395ndash1400 2011

[58] KHiraiwaMUedaH Takeuchi et al ldquoSentinel nodemappingwith thermoresponsive magnetic nanoparticles in ratsrdquo Journalof Surgical Research vol 174 no 1 pp 48ndash55 2012

[59] A S Wadajkar J U Menon Y-S Tsai et al ldquoProstatecancer-specific thermo-responsive polymer-coated iron oxidenanoparticlesrdquo Biomaterials vol 34 no 14 pp 3618ndash3625 2013

[60] R Katoch ldquoProtein purification techniquesrdquo in AnalyticalTechniques in Biochemistry and Molecular Biology pp 149ndash168Springer New York NY USA 2011

[61] S C Tan and B C Yiap ldquoDNA RNA and protein extractionthe past and the presentrdquo Journal of Biomedicine and Biotechnol-ogy vol 2009 Article ID 574398 10 pages 2009

[62] A Orfao and A Ruiz-Arguelles ldquoGeneral concepts about cellsorting techniquesrdquo Clinical Biochemistry vol 29 no 1 pp 5ndash91996

[63] M Urh D Simpson and K Zhao ldquoAffinity chromatographygeneral methodsrdquo inMethods in Enzymology R B Richard andP D Murray Eds chapter 26 pp 417ndash438 Academic Press2009

[64] B Kowalczyk I Lagzi and B A Grzybowski ldquoNanosepara-tions strategies for size andor shape-selective purification ofnanoparticlesrdquo Current Opinion in Colloid amp Interface Sciencevol 16 no 2 pp 135ndash148 2011

[65] I Safarik and M Safarikova ldquoMagnetic nano- and microparti-cles in biotechnologyrdquo Chemical Papers vol 63 no 5 pp 497ndash505 2009

[66] L Xie R Jiang F Zhu H Liu and G Ouyang ldquoApplication offunctionalized magnetic nanoparticles in sample preparationrdquoAnalytical and Bioanalytical Chemistry vol 406 no 2 pp 377ndash399 2014

[67] M Benelmekki and L M Martinez ldquoMagnetophoresis ofiron oxide nanoparticles a tool for synthesis monitoring andbiomagnetic applicationsrdquo inNanotechnologyVol 7 Diagnosticsand Therapeutics chapter 15 Studium Press New Delhi India2013

[68] T Isojima M Lattuada J B Vander Sande and T A HattonldquoReversible clustering of pH- and temperature-responsive Janusmagnetic nanoparticlesrdquoACSNano vol 2 no 9 pp 1799ndash18062008

[69] E A Osborne B R Jarrett C Tu and A Y Louie ldquoModulationof T2 relaxation time by light-induced reversible aggregationof magnetic nanoparticlesrdquo Journal of the American ChemicalSociety vol 132 no 17 pp 5934ndash5935 2010

[70] M A Nash P Yager A S Hoffman and P S Stayton ldquoMixedstimuli-responsive magnetic and gold nanoparticle system forrapid purification enrichment and detection of biomarkersrdquoBioconjugate Chemistry vol 21 no 12 pp 2197ndash2204 2010

[71] J J Lai J M Hoffman M Ebara et al ldquoDual magnetic-temperature-responsive nanoparticles for microfluidic separa-tions and assaysrdquo Langmuir vol 23 no 13 pp 7385ndash7391 2007

[72] A Hoshino N Ohnishi M Yasuhara K Yamamoto and ARondo ldquoSeparation of murine neutrophils and macrophages


by thermoresponsive magnetic nanoparticlesrdquo BiotechnologyProgress vol 23 no 6 pp 1513ndash1516 2007

[73] Q Zhao N Chen D Zhao and X Lu ldquoThermoresponsivemagnetic nanoparticles for seawater desalinationrdquo ACS AppliedMaterials amp Interfaces vol 5 no 21 pp 11453ndash11461 2013

[74] A Razmjou M R Barati G P Simon K Suzuki and HWangldquoFast deswelling of nanocomposite polymer hydrogels viamagnetic field-induced heating for emerging FO desalinationrdquoEnvironmental Science amp Technology vol 47 no 12 pp 6297ndash6305 2013

[75] Y Chen Y Bai S Chen et al ldquoStimuli-responsive compositeparticles as solid-stabilizers for effective oil harvestingrdquo ACSApplied Materials amp Interfaces vol 6 no 16 pp 13334ndash133382014

[76] J J Crassous A M Mihut H Dietsch et al ldquoAdvanced mul-tiresponsive comploids from design to possible applicationsrdquoNanoscale vol 6 no 15 pp 8726ndash8735 2014

[77] G Liu D Wang F Zhou and W Liu ldquoElectrostatic self-assembly of au nanoparticles onto thermosensitive magneticcore-shell microgels for thermally tunable and magneticallyrecyclable catalysisrdquo Small vol 11 no 23 pp 2807ndash2816 2015

[78] A Schmid J S Dordick B Hauer A Kiener M Wubboltsand B Witholt ldquoIndustrial biocatalysis today and tomorrowrdquoNature vol 409 no 6817 pp 258ndash268 2001

[79] G UMarten T Gelbrich andAM Schmidt ldquoHybrid biofunc-tional nanostructures as stimuli-responsive catalytic systemsrdquoBeilstein Journal of Organic Chemistry vol 6 pp 922ndash931 2010

[80] A Saeed N Francini L White et al ldquoA thermoresponsive andmagnetic colloid for 3D cell expansion and reconfigurationrdquoAdvanced Materials vol 27 no 4 pp 662ndash668 2015

[81] P Wang J He P-N Wang and J-Y Chen ldquoPoly (N-isopropylacrylamide)-coated multifunctional nanoparticles forcell trackingrdquo Photomedicine and Laser Surgery vol 28 no 2pp 201ndash205 2010

[82] Z Wang X Ma S Zong Y Wang H Chen and Y CuildquoPreparation of a magnetofluorescent nano-thermometer andits targeted temperature sensing applications in living cellsrdquoTalanta vol 131 pp 259ndash265 2015

[83] M S R Siddiki S Shimoaoki S Ueda and I Maeda ldquoTher-moresponsive magnetic nano-biosensors for rapid measure-ments of inorganic arsenic and cadmiumrdquo Sensors vol 12 no10 pp 14041ndash14052 2012

Submit your manuscripts athttpwwwhindawicom

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CorrosionInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Polymer ScienceInternational Journal of



CeramicsJournal of


CompositesJournal of

NanoparticlesJournal of



International Journal of

Biomaterials


NanoscienceJournal of

TextilesHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Journal of

NanotechnologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

CrystallographyJournal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


CoatingsJournal of

Advances in

Materials Science and EngineeringHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Smart Materials Research



MetallurgyJournal of


BioMed Research International

MaterialsJournal of


Nano

materials


Journal ofNanomaterials


have tunable LCSTs and properties Furthermore the devel-opment of novel orthogonal chemistries [20] to functionalizepolymers with other molecules drugs imaging moietiesand targeting groups or to functionalize nanoparticles withpolymers has brought about new designs and formulationsof composite nanomaterials having multistimuli responsivebehaviors and multimodal features [2]

In this review we surveyed publications focusing onthe design and construction of hybrid composite mate-rials composed of thermoresponsive polymeric shells andmagnetic core particles However the emphasis was givento the application-based studies For the detailed syntheticprocedures and characterizations readers may be referred tothe publications focusing exclusively on material design andengineering rather than applications [21ndash27] Although mostof the publications inherently tend to align with biomedicalapplications [28] new studies have started to appear inenvironmental and chemical sciences such as water treatment[29] and catalysis [30] In 2009 Liu et al have publisheda review article with the biomedical emphasis in this field[31] Similarly Medeiros et al have published a review articlein 2010 covering all types of stimuli responsive magneticparticles in biomedical sciences with little emphasis on ther-moresponsive magnetic particles [32] Therefore we envis-aged that a comprehensive recent review on the applicationsof thermoresponsive magnetic nanoparticles in material andbiomedical sciences will be beneficial to researchers havinginterests in this field

2 Thermoresponsive Magnetic Nanoparticles

Magnetic nanoparticles (MNPs) in particular Fe3O4and

120574-Fe2O3 are heavily utilized platforms in various research

areas especially in biomedical sciences due to their appar-ent biocompatibility and unique size-dependent properties[33] MNPs were widely employed as drug carriers [34]Magnetic Resonance Imaging (MRI) contrast agents [35]hypothermic therapeutics [36] and magnetic separators forcells [37] and biomolecules [38] Integration of MNPs andthermoresponsive polymers into a compositehybrid core-shell system results in multistimuli responsive platformsTherefore manipulation of two external stimuli namelythe temperature and the magnetic field may lead to thedesign of smart devices capable of being turned ldquoONrdquo orldquoOFFrdquo at convenience In the following subsections specificapplications of the hybridMNPsthermoresponsive polymerswill be covered

21 Drug Delivery and Imaging Thermoresponsive polymersin drug delivery applications provide controlled release oftherapeutics with the temperature stimulus Drug loadedpolymers exhibit decreases in their volumes above theirLCST as a result of a phase change from extended coil toglobular form which causes the diffusion of entrapped drugmolecules from polymer particles into the surrounding envi-ronment [11] Incorporation of MNPs into these constructsin essence might provide additional benefits (i) Magneticcore component could be used as an internal heat source as aresult of magnetically induced heating and this could trigger

shrinking of polymer shell [31] (ii) preferential accumulationof the polymers into the targeted locations could be achievedby utilizing magnetic force and this process is known asMagnetic Drug Targeting (MDT) [53] (iii) MRI could bebenefitted for imaging and diagnostic applications [54]

In this regard Purushotham et al have reported formula-tion of a thermoresponsive drug delivery system based on 120574-Fe2O3MNPs [55] PNIPAAm has been coated on the surface

of MNPs by means of dispersion free-radical polymerizationof NIPAM monomers Common therapeutics doxorubicinwas loaded into the polymeric shell (Figure 1) The drugrelease profile of resultant system was tested in vitro undermagnetically induced heating conditions and therapeuticallysignificant amount of drug release was observed Howeverthermally induced drug delivery process has proven to beinefficient Furthermore in vivo MDT was studied usingbuffalo rat model which was implanted with hepatocellularcarcinoma cells in liver After the implantation and thegrowth of the tumor drug loaded particles were injectedthrough the main hepatic artery of the rat model followedby placement of a permanent magnet over the liver forsome period MRI and histology studies have shown efficientlocalization of the particles in the tumoral region and theliver

In another study Kim et al have prepared a magneticplatform composed of poly(N-isopropylacrylamide-co-acrylamide)-block-poly(120576-caprolactone) (P(NIPAAm-co-AAm)-b-PCL) and superparamagnetic iron oxide nano-particles particles (SPIONs) [56] Amphiphilic nature ofthe copolymer favored formation of polymeric micellarstructures in aqueous solution and it was found thatdoxorubicin molecules were encapsulated efficiently bymicelles In vitro drug release profile has been testedthrough alternating the temperature between physiologicaltemperature and LCST (43∘C) of the polymer and it wasshown that the rate of drug release was significant atand above LCST Interestingly amount of the releaseddrugs was significantly higher at LCST with magneticallyinduced heating This phenomenon was attributed to theefficient heat transfer to the polymeric shell from nearbySPIONs while thermal heating of the polymer shell requiredmultistep heat transfer from the surrounding matrix Toassess the applicability of the construct in in vitro cell studiesmagnetic micelles were functionalized with an integrin 1205734antibody which is specific to A9 antigen overexpressed inthe squamous cell carcinoma of the head and neck Theexperiments revealed that magnetic micelles were localizedon the surface of the squamous cells whereas magneticmicelles without the antibody did not interact with thecells However no further studies were reported in terms ofthermally or magnetically induced drug delivery

Hoare et al have formulated a membrane-baseddrug delivery platform composed of ethyl cellulosemembrane matrix SPIONs and a thermoresponsive nanogelwhich was produced by copolymerization of NIPAMN-isopropylmethacrylamide (NIPMAAm) acrylamide(AAm) and NN-methylenebisacrylamide cross-linker [57](Figure 2) LCST of the copolymer was controlled byvarying the monomer ratios With the adjustment of LCST



T lt LCST


T lt LCST

T gt LCST

Aqueousmedia



dehydrated matrix



PNIPAMcoating


(a)

(b) (c)









20nm

(a)

2120583m

(b)

~1 cm

(c)


Nanogel


Exteriorspace

Hydrophobicmatrix


(d)








Mn1minus119909

Zn119909Fe2O4-50 nm





Fe3O4-8 nm




heating [42]











3O4


3O4-PNIPAAm










Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield


LCST



bb

b b

b b

bb

bb

b

bb

b

bb

b b










Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





T lt LCST


T lt LCST

T gt LCST

Aqueousmedia



dehydrated matrix



PNIPAMcoating


(a)

(b) (c)









20nm

(a)

2120583m

(b)

~1 cm

(c)


Nanogel


Exteriorspace

Hydrophobicmatrix


(d)








Mn1minus119909

Zn119909Fe2O4-50 nm





Fe3O4-8 nm




heating [42]











3O4


3O4-PNIPAAm










Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield


LCST



bb

b b

b b

bb

bb

b

bb

b

bb

b b










Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




20nm

(a)

2120583m

(b)

~1 cm

(c)


Nanogel


Exteriorspace

Hydrophobicmatrix


(d)








Mn1minus119909

Zn119909Fe2O4-50 nm





Fe3O4-8 nm




heating [42]











3O4


3O4-PNIPAAm










Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield


LCST



bb

b b

b b

bb

bb

b

bb

b

bb

b b










Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






Mn1minus119909

Zn119909Fe2O4-50 nm





Fe3O4-8 nm




heating [42]











3O4


3O4-PNIPAAm










Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield


LCST



bb

b b

b b

bb

bb

b

bb

b

bb

b b










Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials







Streptavidin

Nitrocellulose

+

b

b

b b

b

b

b

b

b b

b

b

AuNP

AuNP

AuNP

AuNP

AuNP

AuNP

mNP

mNPmNP

mNP

mNP

N

S

Heat aboveLCST

Apply magneticfield


LCST



bb

b b

b b

bb

bb

b

bb

b

bb

b b










Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials






Fe3O4polystyrene-



[46]

Fe3O4-SiO2-80 nm


2MA-co-MAA-co-

VBIDA)Lysosome

15ndash25∘C


[47]




Fe3O4-100 nm








Fe3O4-100 nm


30∘C



Fe3O4ndashdextran-

(Therma-Max) 70 nm


18∘C(UCST)












SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials




SN

Flat sheetmembrane

module

Magnet

HGMS

Ultrafiltration

Product water

Sedimented MNPs

ConcentratedMNPs

Attracted MNPs




Drawsolution

Seawater

Heater






4and














Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials









Abbreviations





Acknowledgments


References




























2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials





















2O4cobalt









































































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



























































CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials























CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials










CeramicsJournal of







Biomaterials




Journal of


Journal of





CoatingsJournal of

Advances in








MaterialsJournal of


Nano

materials



Documents

Review Article Applications of Thermoresponsive Magnetic ...downloads.hindawi.com/journals/jnm/2015/350596.pdf · moresponsive magnetic particles [ ]. e refore, we envis-aged that