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NANOTECHNOLOGY IN DRUG DELIVERY SYSTEMS

A Project Presented to The Faculty of the Department of Chemical and Materials Engineering San Jos State University

In Partial Fulfillment of the Requirements for ENGR 200W class Engineering Reports and Graduate Research

by Priyanka Tiwari November 16, 2011

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. Thats 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. Nanomedicine 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] iv

TABLE OF CONTENTS 1 2 INTRODUCTION ............................................................................................................... 1 LITERATURE REVIEW..................................................................................................... 4 2.1 2.2 Introduction to Literature Review ................................................................................. 4 Types of Nanoparticles in drug delivery system ............................................................ 6 Polymeric Nanoparticles ........................................................................................ 6 Ceramics Nanoparticles ......................................................................................... 7 Metal Nanoparticles ............................................................................................... 7 Liposomes ............................................................................................................. 8 Dendrimers ............................................................................................................ 8 Carbon nanotubes .................................................................................................. 9 Liquid Crystals .................................................................................................... 10

2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.3 3

Toxicological hazards of Nanoparticles ....................................................................... 11

CONCLUSION ................................................................................................................. 12

REFERENCES ......................................................................................................................... 14 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, nanomedicine, 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 1

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 magic 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. 2

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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LITERATURE REVIEW 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).
Period Technology Past (Before Nanotechnology) Emulsion based preparation of micro particles - Micro particles - Micelles - micro and nanocrystals Present (Transition period) Nano fabrication - Microchip systems - Layer-by-layer assembled systems e.g. liposomes - Micro needle transdermal delivery systems Future (Mature Nanotechnology) Nano fabrication

Examples

- 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

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 Biodegradable and non-biodegradable polymers Ceramic nanoparticles Metallic nanoparticles Carried therapeutic agents Amino acids, DNA, RNA, proteins, peptides, low molecular weight compounds DNA, Proteins, high molecular weight compounds Proteins, DNA, anticancer therapeutic agents Application of the system Brain tumor, bone healing, diabetes Advantage Endure drug therapeutic agent for months water-soluble, highly stable Extremely small size, high surface area to carry large dose Possess hydrophobic core, outstanding carrier for water-insoluble medication Effective drug delivery system, stay longer in targeted tissue Can be modified to transmit hydrophobic or hydrophilic drug

Diabetes and liver therapy Cancer therapy

Polymeric miscelles

DNA, proteins anticancer therapeutic agents,

Solid tumors treatment

Liposomes

DNA, Proteins, anticancer therapeutic agents

Tumors treatment, HIV cure, vaccine delivery bacterial infection treatment and HIV therapy

Dendrimers

antibacterial, antiviral therapeutic agents, high molecular weight compounds

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 nonbiodegradable. 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 bodys 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.

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 7

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 8

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, 9

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 bodys 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 physicochemical 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--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.

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 12

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, 2228. 2. Singh, S., Fenniri, H., & Singh, B. (2007). Nanotechnology-based drug delivery systems [Electronic version]. Journal of Occupational Medicine and Toxicology, 3. Park, K. (2007). Nanotechnology: What it can do for drug delivery [Electronic version]. Journal of Controlled Release, 120, 1-3 4. Sahoo, S., & Labhasetwar, V. (2003). Nanotech approaches to drug delivery and image [Electronic version]. Drug Discovery Today, 8, 11121120. 5. Hughes, G. (2005). Nanostructure-mediated drug delivery [Electronic version]. Nanomedicine: Nanotechnology, Biology and Medicine, 1, 2230. 6. Yih,T., & Al-Fandi, M. (2006). Engineered nanoparticles as precise drug delivery systems [Electronic version]. Journal of Cellular Biochemistry, 97, 1184-1190 7. Raghuvanshi , R., Mistra, A., Talwar, G., Levy, R., & Labhasetwar, V. (2001). Enhanced immune response with combination of alum and biodegradable nanoparticles containing tetanus toxoid [Electronic version]. Journal of Micoencapsulation, 18, 723732. 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, 2533. 9. Paul, W., & Sharma, C. (2001). Porous hydroxyapatite nanoparticles for intestinal delivery insulin [Electronic version]. Trends in Biomaterials and Artificial Organs, 14, 3738.

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10. Priyabrata, M., Resham, B., & Debabrata, M. (2005). Gold nanoparticles bearing functional anti-cancer drug and anti-angiogenic agent: A 2 in 1 system with potential application in therapeutics [Electronic version]. Journal of Biomedical Nanotechnology, 1, 224228. 11. Sun, Y., Mayers, T., & Xia, Y. (2002). Template-engaged replacement reaction: A onestep approach to large scale synthesis of metal nanostructure with hollow interior [Electronic version]. Nano Letters, 2, 481485. 12. Hofheinz, D., GnadVog, U., Beyer, U., & Hochhaus, A. (2005). Liposomal encapsulated anti-cancer drugs. [Electronic version]. Anti-cancer Drugs, 16, 691707. 13. Cheng, Y., Xu,Z., & Ma, M & Xu T (2007). Dendrimers as drug carriers: Applications in different routes of drug administration [Electronic version]. Journal of Pharmaceutical Sciences, 97, 123-143. 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]. Cancer Research, 65, 53175324. 15. Prato, M., Kostas, K., & Alberto, B. (2007). Functionalized Carbon Nanotubes in Drug 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. 19. Michaelis, K., Hoffmann, M., Dreis, S., Herbert, E., Alvautdin, R., Michaelis, M., Kreuter, J., & Langer, K. (2006) [Electronic version]. The Journal of Pharmacology and Experimental Therapeutics, 317, 1246-1253. 20. Yih, T., Brunson, W., Wordinger, J., Hu, Z., & Chen, R. (2002). Development of micropump 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

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