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1Institute for Nanoscale Science and Technology (INSAT), University of ... Dentistry and Fixed Prosthodontics, Faculty of Dentistry, University of Jordan, Amman, ... Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, MA ...
Current Nanoscience, 2009, 5, 135-140

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Targeting Nanoparticles as Drug Delivery Systems for Cancer Treatment Karthikeyan Subramani1,*, Hossein Hosseinkhani2, 3, Ameen Khraisat4, Mohsen Hosseinkhani5 and Yashwant Pathak6 1

Institute for Nanoscale Science and Technology (INSAT), University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7ER, UK

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Center for Biomedical Engineering, Massachusetts Institute of Technology (MIT), Boston, MA 02139, USA

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International Research Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

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Department of Conservative Dentistry and Fixed Prosthodontics, Faculty of Dentistry, University of Jordan, Amman, Jordan

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Center of Cancer Systems Biology, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, MA 02135, USA

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Pharmaceutical Sciences, Sullivan University College of Pharmacy, 2100 Gardiner Lane, Louisville, KY 40205, USA Abstract: This review article discusses about the current cancer treatment techniques and the extensive recent research studies done on nanoparticles as carrier systems for the delivery of anticancer drug molecules in cancer treatment. A variety of nanoparticles of different structural and chemical formulations have been tested for their target-specificity and as drug carrier systems. Numerous scientific research works have been performed to test the use of magnetic nanoparticles in the treatment of carcinogenic brain tumour cells and breast cancer cells; colloid gold nanoparticles, liposomes and polymeric micelles as drug delivery systems to target tumour cells and deliver anticarcinogenic drug in a controlled manner. The article also discusses about ceramic nanoparticles and its applications in photodynamic therapy for cancer treatment. The article thus reviews the subject in brief with suitable references to original research articles and review articles discussing the earlier and current research findings about various types of nanoparticles as drug delivery systems in cancer therapy.

Key Words: Nanoparticles, drug delivery systems, cancer therapy, magnetic nanoparticles, colloid gold nanoparticles, liposomes, polymeric micelles. INTRODUCTION

1. CANCER TREATMENT TECHNIQUES

Nanotechnology is the ability to work at the atomic, molecular, supramolecular levels (on a scale of ~1-100nm) in order to understand, create and use material structures, devices and systems with fundamentally new properties and functions resulting from their small structure [1]. Nanotechnology has offered us the ability to design materials with totally new desirable characteristics. Extensive researches are being done worldwide to understand the advantages and scientific limitations of nanoparticles as drug delivery systems. There has been a remarkable progress over the last decade in the development of nanoparticles as effective drug delivery carriers. The various types of nanoparticles that are currently studied for their use as drug delivery systems are polymeric biodegradable nanoparticles that include nanospheres and nanocapsules; ceramic nanoparticles; polymeric micelles; dendrimers; liposomes [2]. The carrier can also be a carbon nanotube [3], a carbon nanohorn [4] or a silica nanoparticle with drug molecules bound to its surface [5]. A magnetic nanoparticle which can be drawn to a particular part of the human body under the influence of magnetic field can serve as an excellent drug delivery system [6]. It can also be an implantable nanoscale device filled with drug molecules encapsulated by nanoporous membrane which can act as tiny turnstiles for releasing the drug [7]. To make these nanoparticles to function as effective drug delivery systems, specific biological molecules like antibodies, enzymes, hormones and pharmaceutical drugs can be coupled structurally to these particles. This review will give an overview on current cancer treatment methodologies and address the recent research works on nanoparticle- based drug delivery systems with a focus on nanoparticle-drug formulations that have been specifically tested for their target-specificity towards cancer cells.

Currently, there are different methodologies available for cancer treatment. But each technique has its own disadvantages and adverse side effects [8, 9]. Surgical treatment (excision of the tumor) is usually the first choice of treatment preferred by physicians. However, it is not effective when the cancer cells have infiltrated the nearby vital organs or have spread to distant parts of the body (metastasis). Surgical excision is preferred for the removal of large tumors. Cryosurgery is another surgical technique used for freezing and killing the abnormal tumour cells. It is an alternative to surgical excision and is used to treat tumors that have not spread and for the treatment of some precancerous or non-cancerous conditions. Chemotherapy is the use of anti-cancer drugs. The drugs are administered as pills, intravenous injection or topically application on skin. Chemotherapeutic drugs may destroy healthy tissue along with destroying the cancer cells and carcinomatous tissue (cytotoxicity). The cytotoxic effect of chemotherapeutic drugs is greatest in organs like bone marrow, gonads, hair follicles and digestive tract which contain rapidly proliferating cells. The adverse effects of chemotherapy include fatigue, nausea, vomiting, alopecia (loss of hair), gastrointestinal disturbance, impaired fertility, impaired ovarian function and bone marrow suppression resulting in anemia, leucopenia and thrombocytopenia [10, 11]. Another technique of cancer treatment is the radiation therapy which uses radiation energy to destroy cancer cells and reduce the size of tumours. Bone marrow transplantation and peripheral blood stem cell transplantation are done to restore stem cells that were destroyed by high doses of chemotherapy or radiation therapy. Immunotherapy (sometimes called biological therapy, biotherapy, or biological response modifier therapy) is a treatment technique that utilizes human body's immune system to destroy cancer cells [12]. The immune system is stimulated by an outside source, such as an antibody, or synthetic immune system proteins or biological response modifiers (BRMs). BRMs include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines, gene therapy and non-specific immunomodulating agents. Recent research works have been con-

*Address correspondence to this author at the Institute for Nanoscale Science and Technology (INSAT), University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7ER, UK; E-mail: [email protected]

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centrating on studying gene therapy for cancer treatment. Gene therapy is an experimental treatment that involves introducing genetic material into the cancer cells to destroy them [13]. Angiogenesis inhibitors are also currently being evaluated in clinical trials. These are chemicals which inhibit the formation of blood vessels (angiogenesis). Angiogenesis plays an important role in the growth and spread of cancer cells [14]. New blood vessels act as a source of oxygen and nutrients to the cancer cells allowing these cells to grow, invade nearby tissue, spread to other parts of human body and form new colonies of cancer cells. Angiogenesis inhibitors are used to prevent the formation of blood vessels and thereby depleting the cancer cells of oxygen and nutrients and thereby resulting in the destruction of cancer cells. Hyperthermia (also called thermal therapy or thermotherapy) is a type of cancer treatment technique in which the cancer cells are exposed to high temperatures (up to 113°F). Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues [15]. By killing cancer cells and damaging proteins and structures within cells, hyperthermia destroys cancer cells [16]. Hyperthermia may make some cancer cells more sensitive to radiation or harm other cancer cells that radiation cannot damage. It can also enhance the effects of certain anticancer drugs. So it is almost used with other forms of cancer therapy, such as radiation therapy and chemotherapy [17]. Hyperthermia is under study in clinical trials. Laser therapy uses high-intensity laser to treat cancer [18]. Laser can be used to shrink or destroy tumors. Laser therapy is most commonly used to treat superficial tumors on the surface of the body or the lining of internal organs. Photodynamic therapy (PDT) is a type of cancer treatment that uses a drug called a photosensitizer or photosensitizing agent [19]. Photosensitizer is activated by light of a specific wavelength. When photosensitizers are exposed to this specific wavelength of light, they produce singlet oxygen which destroys cancer cells. Targeted cancer therapy uses targetspecific drugs that invade cancer cells and block the growth and metastasis of cancer cells by interfering with specific molecules involved in carcinogenesis and tumor growth [20]. 2. ANTI-CARCINOGENIC AGENTS

CHEMOTHERAPEUTIC

In general, anti-carcinogenic chemotherapeutic agents can be divided into three main categories based on their mechanism of action [21]. 2.1. Prevention of Synthesis of pre DNA Molecule Building Blocks DNA building blocks are folic acid, heterocyclic bases, and nucleotides, which are made naturally within cells. All of these agents work to block some step in the formation of nucleotides or deoxyribonucleotides (necessary for making DNA). When these steps are blocked, the nucleotides, which are the building blocks of DNA and RNA, cannot be synthesized. Thus the cells cannot replicate due to impaired DNA synthesis. Examples of drugs in this class include Methotrexate, Fluorouracil, Hydroxyurea and Mercaptopurine. 2.2. By Chemical Damage of DNA in the Cell Nuclei Some chemotherapeutic agents destroy DNA and RNA of cancer cells. They disrupt replication of the DNA and totally halt the replication of DNA or RNA that may stimulate cancer cell formation. A few examples of drugs in this class include Cisplatin, Antibiotics – Daunorubicin, Doxorubicin and Etoposide. 2.3. Disruption of Synthesis or Breakdown of Mitotic Spindles Mitotic spindles serve as molecular railroads with ‘north and south poles’ in the cell when it starts to divide. These spindles are very important because they help to split the newly copied DNA such that a copy goes to each of the two new cells during cell divi-

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sion. These drugs disrupt the formation of these spindles and therefore interrupt cell division. Classic examples of drugs in this class of mitotic disrupters include Vinblastine, Vincristine and Paclitaxel. 3. NANOPARTICLES IN CANCER TREATMENT Nanoparticles are currently studied for their use in detection of cancer at its earlier stage and in targeted anti-cancer drug delivery of the above mentioned drugs. The critical step in cancer treatment is the detection of cancer at its initial stage of carcinogenesis. Results of the numerous researches done in nanotechnology are inspiring the scientific community to discover new innovative noninvasive tools at the nanoscale level for such purposes. Nanoscale cantilevers [22] and quantum dots [23, 24] are being studied as cancer detection tools at the cellular level. If the tumour has not been detected in its early stage, treatment methods should be devised to eradicate the fully developed cancer cells without harming the normal healthy cells of human body. Targeting of nanoparticles can be divided into ‘active’ and ‘passive’ targeting [25]. Active targeting can be further subdivided into ‘chemical/biological’ and ‘physical’ targeting. Chemical/biological targeting involves modification of a nanoparticle surface by chemical/biological tumourspecific ligands. Physical targeting involves directing the nanoparticles to tumour cells under the influence of an external magnetic field. Passive targeting involves modifying the nanoparticle itself without the addition of any ligands or physical methods, thereby increasing the circulation time. This enables accumulation of nanoparticles in tumours by an effect called ‘enhanced permeability and retention effect’ (EPR) effect. The EPR effect utilizes the property by which certain sizes of molecules, typically liposomes or macromolecular drugs, tend to accumulate more in tumour tissue than in normal tissues [26, 27]. In order for the tumour cells to grow quickly, they must stimulate the production of blood vessels (angiogenesis). Tumour cell aggregates of size as small as 150-200 um, start to become dependent on blood supply for nutritional and oxygen supply. These newly formed tumour vessels are usually abnormal in form and architecture. Furthermore, tumour tissues usually lack effective lymphatic drainage. All these factors lead to abnormal molecular and fluid transport dynamics especially for macromolecular drugs. The EPR-effect is even more enhanced by many pathophysiological factors like more vascular endothelial growth factor (VEGF) production by the newly developing capillaries. The EPR effect also provides a great opportunity for more selective targeting of lipid or polymer-conjugated anticancer drugs [28, 29]. The various types of nanoparticles that are currently studied for their use as drug delivery systems are polymeric micelles, magnetic nanoparticles, colloidal gold nanoparticles and ceramic nanoparticles [30-32]. These nanoparticle-based drug delivery systems can be characterized for their localization in tumour cells by coating them with tumour-specific antibodies, peptides, sugars, hormones and anti-carcinogenic drugs, to mention a few. These nanoparticles have been effectively coupled with the above mentioned anti-carcinogenic chemotherapeutic agents and have been tested for their target-specificity. These nanoparticles are superior over the conventionally available drug delivery systems as the chemotherapeutic agents can be targeted to a specified area of the human body by adding nanoscale surface receptors. These receptors specifically recognize the target tissue and bind to it and release the drug molecules [33]. Thus healthy cells can be spared from cytotoxic effects of the drug. Drugs can also be protected from degradation by encapsulating them with nanoparticle coatings [34]. As nanoparticles are extremely small, they can penetrate through smaller capillaries and are easily taken up by cancer cells. This causes efficient drug accumulation at the target site. Use of biodegradable nanoparticles allows sustained drug release over a period of time [35]. Thus nanoparticles as drug delivery systems with enhanced target specificity can overcome the limitations of conventional cancer treatment techniques.

Targeting Nanoparticles as Drug Delivery Systems

3.1. Gold Nanoparticles for Anti-Carcinogenic Drug Delivery Colloidal gold nanoparticles are the most commonly used nanoparticles for anti-carcinogenic drug delivery. Colloidal gold nanoparticles are more biocompatible than other nanoparticles [36]. The physical and chemical properties of colloidal gold nanoparticles allow more than one protein molecule to bind to a single particle of colloidal gold. The use of colloidal gold nanoparticles as drug delivery vectors of tumour necrosis factor (TNF) has been tested in a growing tumour in mice [36]. Although TNF has been evaluated in cancer treatment, it causes adverse effects like hypotension and in some cases causing organ failure resulting in death. But recent researches have shown that when coupled with colloid gold particles, therapeutic amounts TNF can be successfully delivered to destroy the tumour cells in animals [37]. The use of laser to destroy the tumour cells in human breast cancer tissue has been described by a technique of selective nanothermolysis of self-assembling gold nanoparticles [38]. These gold nanoparticles were coated with secondary Ab goat anti-mouse IgG. This structural configuration showed specific localization in the adenocarcinomatous breast cells targeted with primary Ab. Colloidal gold nanoparticles can also function as safe and efficient gene delivery vehicles in gene therapy and immunotherapy of cancer. Plasmid DNA encoding for murine interleukin-2 was complexed with gold nanoparticles [39]. Gold nanoparticles showed significantly higher cellular delivery and transfection efficiency than other gene delivery vehicles. 3.2. Liposomes in Cancer Treatment Liposomes are small artificial spherical vesicles made from naturally occurring non-toxic phospholipids and cholesterol [40]. There are four major types of liposomes. Conventional liposomes are either neutral or negatively charged. Sterically stabilized ‘stealth’ liposomes carry polymer coatings to obtain prolonged circulatory duration. Immunoliposomes have specific antibodies or antibody fragments on their surface to enhance target specific binding. Cationic liposomes interact with negatively charged molecules and condense them to finer structure thereby carrying them externally rather than encapsulating the molecules within [41]. Due to their size, biocompatibility, hydrophobicity and ease of preparation, liposomes serve as promising systems for drug delivery. Their surfaces can be modified by attaching polyethylene glycol units (PEG) to enhance the circulation time in blood stream. Liposomes can also be conjugated with ligands or antibodies to improve their target specificity. Anti-estrogens solubilized within the oily core of liposomes incorporated high amounts of 4-hydroxy tamoxifen (4HT) or RU58668 [42]. This combination was used in the treatment of multiple myeloma as the cancer cells express estrogen receptors and is of particular interest in the treatment of estrogen-dependant breast cancer. In 20-30% of breast cancer cells there is a high amount of human epidermal growth factor-2 (HER2) expression. Anti-HER2 antibodies conjugated immunoliposomes with magnetic nanoparticles were used to treat breast cancer cells with hyperthermia [43]. Such studies demonstrate the potential of liposomes as a drug delivery system in breast cancer treatment. 3.3. Magnetic Nanoparticles in Cancer Treatment Carbon magnetic nanoparticles (CMNP) are made up of spherical particles of 40-50 nm in diameter with iron oxide particles dispersed in a carbon-based host structure [44]. Doxorubicin molecules (DOX) immobilized on activated CMNP formed CMNPDOX conjugates which were demonstrated effective in cancer cell cytotoxicity assays [45]. This showed that CMNPs can be used as effective drug delivery systems. Iron oxide magnetic nanoparticles can also be sheathed with sugar molecules [46]. Therefore these are not recognized by the immune system. When these particles are brought under the influence of an external magnetic field, they heat up the tumour cells and destroy them without affecting the surrounding healthy tissues. A group of researchers have synthesized

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biodegradable magnetic nanoparticles using organic polymers and nanosized magnetites [47]. After the characterization studies, an external magnetic field was used as a guidance system to direct the magnetic nanoparticles to the specified part of the experimental setup. The results of such studies substantiate the theory of targeting magnetic nanoparticles to specific areas of the human body using an external magnetic field. The magnetic nanoparticles can be targeted to specified tumour cells by adding nanoscale surface receptors (targeting moieties). These receptors specifically recognize the target tumour tissue and bind to it and release the drug molecules. Different tumour cells exhibit different cell receptors. Iron oxide nanoparticles can also be coated with amino groups to achieve cell specific delivery of therapeutic agents, for example, to carcinomatous brain cells, without unselectively invading the whole brain. This concept has been demonstrated in a study about functionalized superparamagnetic iron oxide nanoparticles and the interaction with the brain cells [48]. An approach of localizing the iron oxide nanoparticles to specific cell receptors has been studied by functionalizing them with glycoproteins like lactoferrin and ceruloplasmin [49]. In breast cancer tissue, luteinising hormone release hormone (LHRH) receptors are expressed predominantly. So, to localize the iron oxide nanoparticles to the cancerous breast tissue the magnetic nanoparticles can be conjugated with luteinising hormone release hormone. Such an approach [50] has demonstrated the target specificity the iron oxide nanoparticles in breast cancer treatment. These approaches prove that magnetic nanoparticles can be functionalized with suitable targeting moieties to localize them specifically to tumour cells under the influence of an external magnetic field. 3.4. PEG Polymeric Micelles as Drug Delivery Systems Polymeric micelles serve as a novel drug delivery system due to their target specificity and controlled release of hydrophobic anticancer drugs [51]. Poly (ethylene glycol) PEG-based micelles are biocompatible and biodegradable. Effective drug delivery of cytotoxic drugs to cancer cells using PEG polymeric micelles has been demonstrated by conjugating Doxorubicin with poly (ethylene glycol)-poly (, -aspartic acid) block copolymer [52]. Doxorubicin also known as Adriamycin was physically entrapped and chemically bound to the core of the polymeric micelle. Due to reduced uptake by the reticuloendothelial system (RES), this drug carrier had a prolonged circulation time in the blood stream. Localization to the cancer cells can be achieved by linking monoclonal antibodies, sugars and biotin or tumour specific peptides to the polymeric micelles [53]. PEG-coated biodegradable nanoparticles can be coupled with folic acid to target folate-binding protein which is a soluble form of folate protein which is over expressed on the surface of many tumour cells. These folate linked nanoparticles have been tested and confirmed for their selective target binding [54]. These studies demonstrate the potential of PEG polymeric micelles as a novel drug delivery system in cancer treatment. 3.5. Ceramic Nanoparticles in Photodynamic Therapy Ceramic nanoparticles are made from calcium phosphate, silica, alumina or titanium. These ceramic nanoparticles have certain advantages like easier manufacturing techniques, high biocompatibility, ultra-low size (less than 50nm) and good dimensional stability [55]. These particles effectively protect the doped drug molecules against denaturation caused by changes in external pH and temperature. Their surfaces can be easily modified with different functional groups and can be conjugated with a variety of ligands or monoclonal antibodies in order to target them to desired sites [56]. These nanoparticles can be manufactured with the desired size, shape and porosity. A ceramic nanoparticle does not undergo swelling or porosity changes caused by fluctuations in temperature or pH and are small enough to evade the reticuloendothelial system (RES). The application of ultrafine silica-based nanoparticles which are ~35 nm

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in diameter with photosensitive anti-carcinogenic drugs encapsulated within has been described [57]. These ceramic nanoparticles have been used to destroy cancer cells by photodynamic therapy. When activated by light of suitable wavelength of 650 nm, the drug produces singlet oxygen which necroses the tumour cells. This concept of using silica nanoparticle platforms which can attach to the external surface of tumour cells and deliver photosensitizer like m-THPC (meta-tetra (hydroxyphenyl)-chlorin) and singlet oxygen induced cancer cell apoptosis has also been demonstrated [58]. 4. NANOBIOTECHNOLOGY-BASED APPROACH TOWARDS DRUG DELIVERY IN CANCER TREATMENT Discussed above are the few most promising groups of nanoparticles and their applications in drug delivery for cancer treatment. There are numerous other nanobiotechnology-based approaches being developed to formulate nanoparticles as carriers of anti-carcinogenic agents. These include dendrimers, chitosan nanoparticles, low density lipoproteins (LDL), nanoemulsions, nanolipispheres, nanoparticle composites, polymeric nanocapsules, nanospheres and nanovesicles. Their applications in nanoencapsulation and targeted drug delivery of anti-cancer drugs in combination with radiotherapy, laser therapy, thermotherapy, photodynamic therapy, ultrasound therapy and nanoparticle-mediated gene therapy have been extensively reviewed in the earlier literature [59]. 5. NANOPARTICLE-BASED DELIVERY OF SPECIFIC ANTI-CARCINOGENIC DRUGS Methotrexate, a potent anticancer drug has been coupled with polybutylcyanoacrylate nanoparticles of different sizes from 70-345 nm and tested for their ability to overcome blood-brain barrier in the treatment of brain cancer. This study showed that polysorbate 80-coated polybutylcyanoacrylate nanoparticles of diameter below 100 nm can effectively overcome the blood-brain barrier [60]. Research studies done on experimental rats have demonstrated that the nanoparticle formulation consisting of poly (amidoamine) modified with PEG-500 had the ability of sustained release of 5-Fluorouracil and was target specific [61]. PLGA-mPEG nanoparticles were used as a carrier for Cisplatin and this study [62] showed that PLGAmPEG effectively delivered the drug to human prostate cancer cells. PLGA nanoparticles have been shown as effective carriers of Doxorubicin [63]. Positively charged polysaccharide chitosan nanoparticles have also been tested for their target-specificity to deliver doxorubicin [64]. PLGA nanoparticles containing vitamin E have also been tested for their drug-carrying potential for Paclitaxel, an anticarcinogenic drug which interferes with mitotic spindles and therefore inhibiting cell division [65]. Nitrocamptothecin, an alkaloid drug belonging to a class of anticancer agents called topoisomerase inhibitors have also been target-specifically delivered to the cancer cells by PLGA nanoparticles [66]. Trastuzumab (more commonly known under the trade name Herceptin) is a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor which are over expressed in breast cancer cells. Human Serum Albumin (HSA) nanoparticles were used as drug delivery systems and this study showed that a stable and biologically active system like albumin can be utilized in cancer treatment [67]. Another drug belonging to the same category and used in breast cancer treatment is Tamoxifen. Poly (ethylene oxide)-modified poly (caprolactone) polymeric nanoparticles (PEO-PCL) have been tested for their target specificity as a carrier for tamoxifen. These research studies prove that a wide variety of nanoparticles can effectively function as drug delivery systems for anti cancer drugs and thereby eliminating the adverse effects of these pharmaceutical agents.

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6. LIMITATIONS OF NANOPARTICLES AS DRUG DELIVERY SYSTEMS The science and knowledge that the scientific community has today about nanotechnology and its potential versatile applications is only based on the researches done in the laboratories. These researches are being conducted to understand how matter behaves at the nanoscale level. Factors and conditions governing the behaviour of macrosystems do not really apply to the nanosystems. The major limitations and technological hurdles faced by nanotechnology and its applications in the field of drug delivery should be addressed [68, 69]. Scientific community hasn’t yet understood completely how the human body would react to these nanoparticles and nanosystems which are acting as drug carriers. Nanoparticles have larger surface area when compared to their volume. Friction and clumping of the nanoparticles into a larger structure is inevitable which may affect their function as a drug delivery system. Due to their minute size these drug carriers can be cleared away form the body by the body’s excretory pathways. When these are not excreted, larger nanoparticles can accumulate in vital organs causing toxicity leading to organ failure. Polymeric micelles were reported to cause acute hypersensitivity reactions in a few animal studies. Liposomes have certain drawbacks like being captured by the human body’s defense system. The drug loading capacity of liposomes is being tested by researchers and still remains inconclusive. A few studies have shown post-treatment accumulation of the nanoparticles in skin. Studies on crystalline silver nanoparticles in therapeutic application raised the possibility of cytotoxicity in lesioned skin or growing human fibroblasts and keratinocytes [70, 71]. Recent study in mice revealed that tissue distribution of gold nanoparticles is size-dependent with the smallest nanoparticles (15-50 nm) showing the most widespread organ distribution including blood, liver, lung, spleen, kidney, brain, heart and stomach [72]. Once the nanoparticles are administered into the human body, they should be controlled by an external control preventing them from causing adverse effects. These drug delivery technologies are in various stages of research and development. It is expected that these limitations can be overcome and the discoveries to come into practical use within the next 5-10 years. 7. CONCLUSION Discussed in this review are the research works done in the past decade in targeting novel nanoparticles towards the treatment of cancer. This study has expanded tremendously in the past few years as new nanoparticle carrier systems and anti-cancer drugs are being discovered. The uses of nanoparticles for early diagnosis of cancer and in gene therapy have been extensively reviewed in the literature [73-77]. A few of these innovative treatment techniques have made their way into clinical trials. There is a lot more to be done to in order to treat or perhaps prevent advanced cancer by treating it in an early stage. This will require superior detection and targeting methods which many of the researchers are pursuing on nanoparticle based drug delivery systems. These research studies in nanotechnology will definitely pave the way for early detection and prevention of cancer thereby improving the life and quality of cancer patients. REFERENCES [1] [2] [3]

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Revised: December 31, 2008

Accepted: January 18, 2009