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8/3/2019 Nanotechnology in Drug Delivery Systems - Ammendments
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NANOTECHNOLOGY IN DRUG DELIVERY SYSTEMS
A Project
Presented to
The Faculty of the Department of Chemical and Materials Engineering
San José State University
In Partial Fulfillment
of the Requirements for ENGR 200W class
Engineering Reports and Graduate Research
by
Priyanka Tiwari
November 16, 2011
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© 2011
Priyanka Tiwari
ALL RIGHTS RESERVED
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The Designated Committee Approves the Project Titled
NANOTECHNOLOGY IN DRUG DELIVERY SYSTEMS
By
Priyanka Tiwari
Approved for the Department of Chemicals and Materials
Engineering
SAN JOSE STATE UNIVERISTY
May 2013
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ABSTRACT
NANOTECHNOLOGY IN DRUG DELIVERY SYSTEMS
by Priyanka Tiwari
Recently there is a lot of buzz about nanotechnology. The field allows manipulation of
different properties of matter at an extremely small scale. That¶s why nanotechnology is not
limited to a specific area of research. The field has its application in a variety of disciplines such
as medicine, electronics, food, military, fuels, consumer products, space etc. ³Nanomedicine´ is
one such field that employs the use of nanoparticles in diagnosis, treatment and prevention of
deadly diseases such as cancer, tumor, TB etc. This project discusses the various nanoparticles
used in drug delivery systems along with the hazards associated with them.
[To be completed]
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TABLE OF CONTENTS
1 INTRODUCTION ............................................................................................................... 1
2 LITERATURE REVIEW..................................................................................................... 4
2.1 Introduction to Literature Review ................................................................................. 4
2.2 Types of Nanoparticles in drug delivery system ............................................................ 6
2.2.1 Polymeric Nanoparticles ........................................................................................ 6
2.2.2 Ceramics Nanoparticles ......................................................................................... 7
2.2.3 Metal Nanoparticles ............................................................................................... 7
2.2.4 Liposomes ............................................................................................................. 8
2.2.5 Dendrimers ............................................................................................................ 8
2.2.6 Carbon nanotubes .................................................................................................. 9
2.2.7 Liquid Crystals .................................................................................................... 10
2.3 Toxicological hazards of Nanoparticles ....................................................................... 11
3 CONCLUSION ................................................................................................................. 12
REFERENCES ......................................................................................................................... 14
1.
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1 INTRODUCTION
The scope of this project is to analyze the application of nanotechnology in drug delivery
system. Man has always been working hard to find an antidote for incurable diseases to save life
and increase life span of forthcoming generations. He has succeeded in this quest by finding
therapy for several fatal diseases such as polio, chicken pox, malaria, measles, pertussis and
typhoid. However, man is still fighting with diseases such as cancer, tumor and HIV that are life
threatening and have no permanent remedy for their cure. The project thus highlights the scope
of nanotechnology as an alternative solution in building efficient drug delivery system. This will
eventually help in fighting with these deadly diseases. This topic is selected for ENGR 200W
project since the subject has a vast amount of research potential. I feel that this project will help
me understand integration processes of nanotechnology and biochemical engineering in the
medical field.
The scope of this field is remarkably wide since several kinds of nanoparticles are under
development. These particles are developed to provide treatment for lethal diseases such as
cancer and tumor. This project is limited to study to different kinds of nanoparticles that are used
in drug delivery system and hazards associated with them. Future work on this project will
involve detail study of working mechanism of these particles in the human body.
All disciplines of medical science such as tissue engineering, genetic engineering, gene
therapy, biotechnology and stem cells have now started exploring the vast opportunities provided
by nanotechnology. In addition to this, ³nanomedicine´, which is a burgeoning field, also has a
tremendous potential for revolutionizing the current diagnostic and prevention systems used in
the medical field. A key challenge faced by the pharmaceutical industry is to develop clinically
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useful drugs. These drugs should selectively repair the damaged cells in the human body without
altering characteristics of healthy cells. Conventional drug delivery systems always raise a
question of side effects that the drug has on the human body. For e.g., Cancer chemotherapy is
highly effective way of destroying cancer cells. However, the treatment exhibits adverse life
threatening effects on the normal functioning healthy cells. Thus, significant research is going
on to improve current drug delivery system. The breakthrough in this area is the use of
nanofabrication methods to create nanoparticles that can be used in drug delivery.
Dr. Paul Ehrlich, in 1891, coined the term ³magic bullet´. The concept presented by him first
explained drug targeting hypothesis. Drug targeting aims at delivering drug to the right place in
the body, at an accurate concentration, for an appropriate period. It is highly difficult to
determine essential characteristics for drug efficacy since different drug characteristics differ
significantly in chemical composition, hydrophilicity, protein attachment and molecular mass.
Poor physiochemical properties of drugs lead to poor solubility and poor distribution of
therapeutic compounds in the blood stream. This also results in weak interaction of drug and
affected cell. With new drug delivery system, scientists have the ability to reach a specific
damaged cell which also improves drug cell interaction.
Scientists are investigating various types of nanoparticles to use in drug delivery systems.
Materials used to design these particles have distinctive molecular structure. Nanoparticles are
effective drug vehicles that can cure and eliminate a disease from its root. Current research in the
medical field provides a solution for treatment of fatal diseases such as HIV, cancer,
tuberculosis, and diabetes. The method thus provides a short term solution for these diseases and
eventually the patients suffer death. Targeting cancer cells, using nanoparticles laden with
anticancer agents, provides a promising technique to fight the disease.
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Vaccination is another area of examination that can be advanced from the use of
nanoparticles. Recently Cui et al has proposed an innovative cancer vaccine system by making
use of nanoparticles. Their group tested the immunity system in mice by using Liposome
polycation pDNA (LPD) nanoparticles to carry a resilient peptide antigen. The results obtained
on application demonstrated an extremely high efficacy of the novel method compared to the
traditional vaccination modes. Thus, nanoparticles vaccine delivery system helps to augment in
vivo effectiveness of the coming generation vaccines. Research is currently going on in
developing new, powerful and effective drugs to cure diseases. The next generation drugs will
have improved solubility, better intestinal absorption, improved targeting and better in vivo
stability. Scientists are working on creating hybridized nanoparticles to bring next generation
drugs. The hybridization process of these nanoparticles is yet in its initial stages. Nanoparticles
are loaded with drugs via encapsulation and surface attachment. The attachment technique is
determined by material and architecture of nanoparticles, drug type and their targeted location
i.e., the affected cells.
Figure 1: Untargeted drug delivery Vs. Targeted Drug Delivery. Sarabjeet et al., 2007.
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2 LITERATURE REVIEW
2.1 Introduction to Literature Review
There has been a significant improvement in the drug delivery system from past three
decades. Drug delivery technology is thus divided into three categories past (before
nanotechnology revolution), present (transition period) and future (mature nanotechnology).
Table 1 shows the evolution of drug delivery system with advancement in nanotechnology.
Table 1. Advancement in drug delivery with nanotechnology revolution. (Kinam Park,
2008).
PeriodPast (Before
Nanotechnology)
Present (Transition
period)
Future (Mature
Nanotechnology)
Technology
Emulsion based
preparation of micro particles
Nano fabrication Nano fabrication
Examples
- Micro particles- Micelles- micro and
nanocrystals
- Microchip systems
- Layer-by-layer assembled systemse.g. liposomes
- Micro needle
transdermal deliverysystems
- Nano/micro machines
for scale-up production
Nanoparticles used in drug delivery system are fabricated using metals, polymers, ceramics
and biological molecules. Sahoo et al., 2003 presented that the structures of nanoparticles can be
spherical, tubular, branched or shell type. Further Hughes G, 2005 found that these structures
provide unique features to the drug delivery carriers that make them appropriate for a particular
therapy. Yih.C and Fandi. M, 2006 presented the challenges faced by various types of
nanoparticles in different therapies. This literature review discusses different types of
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nanoparticles currently available in drug delivery system. It also tries to look into the hazards
associated with the use of nanoparticles as drug vehicles.
Table 2. Nanoparticles in drug delivery systems. (Yih and Fandi , 2006 [6])
Nanoparticles as
drug carriers
Carried therapeutic
agents
Application of the
system
Advantage
Biodegradable andnon-biodegradable
polymers
Amino acids, DNA, RNA, proteins, peptides, lowmolecular weight
compounds
Brain tumor, bonehealing, diabetes
Endure drugtherapeutic agent for months
Ceramic
nanoparticles
DNA, Proteins, high
molecular weight
compounds
Diabetes and liver
therapy
water-soluble,
highly stable
Metallic
nanoparticles
Proteins, DNA, anti-
cancer therapeutic agents
Cancer therapy Extremely small
size, high surfacearea to carrylarge dose
Polymeric miscelles DNA, proteins anticancer therapeutic agents,
Solid tumorstreatment
Possess hydrophobiccore,
outstanding carrier for water-insoluble
medication
Liposomes DNA, Proteins, anticancer
therapeutic agents
Tumors treatment,
HIV cure, vaccine
delivery
Effective drug
delivery system,
stay longer in targeted tissue
Dendrimers antibacterial, antiviraltherapeutic agents,
high molecular weightcompounds
bacterial infectiontreatment and HIV
therapy
Can be modified totransmit
hydrophobic or hydrophilic
drug
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2.2 Types of Nanoparticles in drug delivery system
2.2.1 Polymeric Nanoparticles
Polymeric nanoparticles used as drug delivery vehicles can be either biodegradable or non-
biodegradable. These nanoparticles can be formed from two methods i.e., polymerization of
monomers and through dispersion of polymers. Significant research is dedicated to develop
biodegradable nanoparticles. Raghuvanshi R et al., 2001 discovered that the polymeric particles
can be easily designed into various shapes and sizes. Biodegradable nanoparticles are best for
use because they can be easily degenerated in the body after delivering drug to the specific cell.
Moreover the particles are capable of carrying various therapeutic compounds such as amino
acids, peptides, proteins, DNA and RNA. In addition to this, the sensitivity of these particles to
highly acidic body environment marks them an ideal candidate for drug delivery systems. The
applications of the particles range from treatment of various types of tumors, vaccination
methods, bone disorders and diabetes. The nanoparticles can be loaded with drug in two ways.
One method is to mix the drug to the nanoparticles during particles formation. The other way is
to adsorb the drug in nanoparticles by incubating the particles in the drug solution. Better
entrapment of drug result from the incorporation process over adsorption method.
Non-biodegradable polymers such as Polymeric micelles are also used as carriers for various
drugs. The spherical structure of micelle is highly stable in human body¶s biological
environment. Thus, the particles aid easy drug delivery to the targeted site. The nanoparticles are
excellent carriers for water insoluble drugs due to the presence of hydrophobic part in the
nanostructure. Therefore, due to their extremely small size (<100nm), the particles can be easily
engineered for attachment with specific drug.
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2.2.2 Ceramics Nanoparticles
Ceramic nanoparticles are ideal candidates for biomaterial applications. This is because the
particles are pretty much compatible with the body fluids and tissues. These nanoparticles are
inorganic and bear high porosity. Ceramic nanoparticles also possess the flexibility of easy
modification with desired porosity and size. Some of the examples are silica, alumina and titania
which are used in cancer. Roy et al., 2003 [8] studied that nanoparticles doped in silica can be
used to fight cancer from photodynamic therapy. Paul and Sharma, 2001 [9] investigated that
with entrapment of insulin in hydroxyapatite, scientists can develop oral insulin. This will help
diabetic patients in getting rid of recurring intake of insulin injections. Ceramics are also widely
used in dentistry as a substitute for bone. These particles found their medical application in
human body way back in 1920. The applications of ceramics in dental problems and other
medical ailments include: repair of bone related defects, treatment of periodontal defects, ear and
eye implant. As the ceramic nanoparticles are biocompatible, these are highly utilized as delivery
systems for drugs and chemicals.
2.2.3 Metal Nanoparticles
These nanoparticles are extremely small in size (<50nm). Hence they have very high surface
to volume ratio which makes them an ideal carrier for high drug dose. Metallic nanoparticles can
also be surface modified by introducing functional groups into their structures. This helps in
improving their surface properties. Priyabrata et al., 2005 [10] presented that composite systems
of gold nanoparticles can be made through functionalization. The composite gold nanoparticles
can carry both anti-angiogenic and anticancer agent simultaneously. The enhanced power of
these particles destroys tumor cells effectively and also keeps a check on the growth of any other
type of tumor. Sun et al., 2002 [11] proposed encapsulation of drug inside the hollow core of
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metal nanoshell. The method used an external infrared light source by nanoparticles to release
drug to the target site. Other than nanoshells and nanospheres, gold nanorods and gold nanocages
can also be formed. The uniqueness of gold nanoparticles is attributed to its optical properties
which can be utilized for therapeutic and imaging applications.
2.2.4 Liposomes
Liposomes are another kind of nanoparticles used in drug delivery systems. Liposomes are
spherical shaped lipid molecules. They have a bilayered membrane structure. These are made up
of natural or synthetic amphiphilic lipid molecules that have an excellent capability to (a)
efficiently encapsulate hydrophilic and hydrophobic therapeutic agents, (b) protect the
encapsulated drugs from external effects and conditions, (c) get functionalized with ligands
which are used to target specific cells and tissues, (d) be enclosed with biocompatible polymers.
These particles are fabricated from cholesterol and phospholipids. These natural particles can be
easily engineered and self-assembled due to the presence of hydrophobic part. The
characteristics are thus altered by selecting the lipid (hydrophobic group) of choice during the
production. Liposomes are considered as harmless drug delivery vehicles as they are natural
materials. Hofheinz et al., 2005 [12] investigated that liposomes can be used to carry anticancer
drugs. The drug carriers are highly efficient since they target the cancer cells without causing any
harm to healthy cells.
2.2.5 Dendrimers
Dendrimers are synthetic polymers that have structures like a tree or star. They have a central
core, inner branches and terminal groups at their surface. Cavities present in the core and inner
branches of dendrimers can be modified to transport hydrophilic and hydrophobic drugs. Yiyun
etal., 2007 [13] redefined two approaches used to synthesize dendrimers. These methods are
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known as divergent method and convergent method. The former employs a bottom up approach
to create dendrimers starting from core towards the surface. The latter follows the top down
approach and create dendrimers from circumference to the core. The choice of the method is
governed by the type of structure required. Star shaped dendrimers are highly used to load drugs.
This is because the drug molecules can be easily attached to either interior (core) or to the
surface groups of dendrimers. Latallo et al., 2005 [14] performed in vivo study to show that
dendrimers can be loaded with anti-cancer drugs to fight tumor cells. Other unique
characteristics of dendrimers are monodispersity characteristics and modifiable surface
functionality. These properties mark them as extremely beneficial compounds for drug delivery.
2.2.6 Carbon nanotubes
Maurizio et al., 2007 [15] proposed that functionalized carbon nanotubes can be used for
efficient drug delivery. Recently among various nanoparticles, carbon nanotubes (CNT) have
emerged as an efficient and latest tool for carrying therapeutic agents to different parts of the
body. Carbon nanotubes have cavities in their atomic structure that makes them an ideal
candidate for drug encapsulation. CNT are easy to functionalize with small organic materials
such as nucleic acids, amino acids, peptides, proteins, and can be used to deliver the therapeutic
drugs to the affected cells and organs. As functionalized CNT exhibits low toxicity, their use
presents a great potential in the field of nanomedicine. Thus functionalization of CNT with
organic compounds has unlocked new prospects in the study of their biological properties.
Toxicity of pure carbon nanotubes always raises concern on their implementation as drug
carriers. First, the biocompatibility of these nanotubes has to be established. Since pristine CNT
(non-functionalised CNT) CNT are highly toxic, due to their insoluble nature, it is of prime
importance to validate the solubility of functionalized CNT in physiological medium. Secondly,
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functionalized CNT have very high tendency to cross cell membranes. The CNT has a unique
chemistry that allows the possibility of hosting more than one function on a single tube. This
offers the usage of targeting molecules, therapeutic agents, reporter molecules, drugs at the same
time. Even though CNT are not fully operational for clinical use, these novel carriers hold
immense potential for drug delivery systems and deserve further examination.
2.2.7 Liquid Crystals
Liquid crystals are those materials that flow like a liquid by maintaining an ordered crystal
like structure. The use of liquid crystals in electronic industry (LCD TV screen) is well known.
These nanoparticles also find application in nanomedicine as a tool for drug delivery systems.
This is because of their enhanced capability to penetrate skin, cells and other tissues. Moreover
they have the ability for timed release of drug.
The liquid crystals are modeled after their success in pharmaceutical industry for biological
systems. Our cells and tissues are also made up of natural liquid crystals called thelyotrophic
molecules. These compounds are necessary elements for DNA, cholesterol and phospholipid
membranes.
Some liquid crystal drugs have found their application in treatment of viral infections and
tumors in bladder and prostate cancer. Liquid crystal pharmaceuticals provide vast potential for
transdermal applications. This is because of their ability to target inflamed cells and tissues.
Tolecine is an example of liquid crystal pharmaceutical which is an anti-tumor drug. Tolecine
possesses antibacterial and antiviral characteristics which help in preventing abnormal tumor
growth.
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2.3 Toxicological hazards of Nanoparticles
From all standpoints, brain is considered as the most challenging organ for nanoparticles drug
delivery. The occurrence of degenerative diseases of brain is high in aging population. The blood
brain barrier is considered as the gatekeeper to exogenous substances in human body. The
pharmaceuticals drugs generally do not cross the blood brain barrier. This is because our body¶s
endothelial barrier is especially tight and thus it can only be passed through endogeneous blood
brain barrier transporters in normal conditions. Koziara etal., 2006 [16] proposed that the barrier
properties may get compromised during drug delivery process providing a conduit for
nanoparticles to enter in brain. The toxic effect of nanoparticles on cerebral endothelial cells was
suggested as the cause of blood brain barrier passage. The effect was however specific to certain
nanoparticles. Kreuter et al., 2003 [17] pointed out that drug is associated physically to the
nanoparticle for delivering of drug to the brain. While evaluating nanoparticles with different
surface properties, it was found that neutral and low concentration anionic nanoparticles have no
effect on the blood brain barrier integrity. On the other hand, high concentrations of cationic and
anionic nanoparticles were found toxic to this integrity. Thus it was concluded that surface
charges present on nanoparticles are toxic for brain distribution contours. Kreuter, 2004 [18]
proposed that polysorbate coated nanoparticles cause the transportation of drugs across the blood
brain barrier. Additional investigations by Michaelis et al., 2006 [19] presented that
apolipoprotein-E is also responsible for passage of drugs across blood brain barrier. It was
suggested that brain capillary endothelial cells recognize and interact with lipoprotein receptors
and thus cause the brain intake of the drug.
Nanoparticles have unique surface properties due to their extremely small size. As surface
comes into the contact with the body tissue, these properties need to be determined from
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toxicological perspective. Currently there are many procedures for drug evaluation to detect any
hazard associated with the use of nanoparticles. However it is not safe to assume that these
methods will detect all potential threats. In addition to this, nanoparticles have different physico-
chemical characteristics when compared to micro particles. This can lead to changed body
distribution, and activation of blood coagulation pathways. Therefore it is important to give
special attention to kinetics and distribution of nanoparticles. It is also essential to test the
toxicity of non-drug loaded nanoparticles vis-à-vis toxicity determination for whole drug
formulation. This is particularly important when non-biodegradable nanoparticles are used for
drug delivery applications. Nanoparticles have adverse effects on cardiovascular system of
human body and brain. In addition to this, the particles also have immunological and cellular
effects on the body.
3 CONCLUSION
Although there has been a significant research in the development of nanoparticles, yet the
quest for developing fully functioning efficient drug delivery system is going on. Further
research and clinical trials are required to accomplish the goal of using nanoparticles as drug
delivery vehicles. The success of these trials will be a key contributor in promotion and growth
of this novel therapy system. Scientists are constantly developing new nanoparticles along with
the researching on various encapsulation methods to bind these particles with the drug
effectively. This provides a clear indication that future drug delivery system has substantial
promise. Current challenges confronted in this area are loading nanoparticles, regulating the drug
discharge profile, and guiding nanoparticles systems to the anticipated target. In addition to this,
the use of non-biodegradable nanoparticles also increases the risk of accumulation of these
compounds into the body thereby passing into blood brain barrier. A high concentration of these
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particles in the body poses serious side effects. Therefore, there is a high need of performing in
vivo toxicological research to avoid such a scenario.
It is anticipated to develop self-actuated therapy for future drug delivery systems. Yih et al.,
2005 [20] worked on development of BioMEMS (bio-micro electro mechanical systems)
micropumps for localized drug delivery systems in a controlled way. Hydrogel is one such
example . The best part with these systems is the automatic determination of drug dosage
through sensory systems. Thus, it is highly essential to evaluate effectiveness of these systems
when they are encapsulated. Thus from our literature review, we can conclude that the application of Nanotechnology in
medicine and drug delivery systems is spreading rapidly. There is a lot of scope in improvement
of nanoparticles driven drug delivery. With extensive research going on in this field, the day is
not far when we will have fully matured nanotechnology based drug delivery system.
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REFERENCES
1. Cui, Z., Han, S., Padinjarae, D., & Huang, L. (2005). Immunsotimulation mechanism of
LPD nanoparticles as a vaccine carrier [Electronic version]. Molecular Pharmaceutics, 2,
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2. Singh, S., Fenniri, H., & Singh, B. (2007). Nanotechnology-based drug delivery systems
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Sahoo, S., & Labhasetwar, V. (2003). Nanotech approaches to drug delivery and image
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systems [Electronic version]. Journal of Cellular Biochemistry, 97, 1184-1190
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immune response with combination of alum and biodegradable nanoparticles containing
tetanus toxoid [Electronic version]. Journal of Micoencapsulation, 18, 723±732.
8. Roy, I., Mitra,S., Maitra, A., & Mozumdar, S. (2003). Calcium phosphate nanoparticles
as novel non-viral vectors for targeted gene delivery [Electronic version]. International
Journal of Pharmaceutics, 250, 25±33.
9. Paul, W., & Sharma, C. (2001). Porous hydroxyapatite nanoparticles for intestinal
delivery insulin [Electronic version]. Trends in Biomaterials and Artificial Organs, 14,
37±38.
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10. Priyabrata, M., Resham, B., & Debabrata, M. (2005). Gold nanoparticles bearing
functional anti-cancer drug and anti-angiogenic agent: A µµ2 in 1¶¶ system with potential
application in therapeutics [Electronic version]. Journal of Biomedical Nanotechnology,
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14. Latallo, J., Candido, K., Cao, Z., Nigavekar, S., Majoros, I., Thomas, T., Baglogh, L.,
Khan, M., & Baker, J. (2005). Nanoparticles targeting of anticancer drug improves
therapeutic response in animal model of human epithelial cancer [Electronic version].
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Design and Discovery [Electronic version]. Accounts of chemical research, 41, 60-68.
16. Koziara, M., Lockman, P., Allen, D., & Mumper, R. (2006). The blood brain barrier and
brain drug delivery [Electronic version]. Journal of nanoscience and nanotechnology, 9,
2712 ± 2735.
17. Kreuter, J., Ramge, P., Petrov, V., Hamm, S., Gelperina, S., Engelhardt, B., Alvautdin,
R., Briesen, H., & Begley, D. (2003). Direct evidence that polysorbate 80 coated
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nanoparticles deliver drugs to the CNS via specific mechanisms require prior binding of
drugs to the nanoparticles [Electronic version]. Pharmaceutical Research, 20, 409-416.
18. Kreuter, J. (2004). Influence of the surface properties on nanoparticle-mediated transport
of drugs to the brain [Electronic version]. Journal of Nanoscience and Nanotechnology,
4, 484-488.
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Yih, T., Brunson, W., Wordinger, J., Hu, Z., & Chen, R. (2002). Development of micro-
pump for localized delivery of controlled drug release hydrogel nanoparticles to improve
cancer and glaucoma treatment [Electronic version]. Nanomedicine: Nanotechnology,
Biology and Medicine, 31, 74-80