For bulk materials larger than one micrometre the percentage of atoms at the surface is minuscule relative to the total number of atoms of the material. The interesting and sometimes unexpected properties of nanoparticles are not partly due to the aspects of the surface of the material dominating the properties in lieu of the bulk properties. Nanoparticles exhibit a number of special properties relative to bulk material. For example, the bending of bulk copper (wire, ribbon, etc.) occurs with movement of copper atoms/clusters at about the 50 nm scale.

Nanoparticle exerts its site-specific drug delivery by avoiding the reticuloendothelial system, utilizing enhanced permeability and retention effect and tumor-specific targeting. These carriers are designed in such a way that they are independent in the environments and selective at the pharmacological site. The formation of nanoparticle and physiochemical parameters such as pH, monomer concentration, ionic strength as well as surface charge, particle size and molecular weight are important for drug delivery. Further, these nanoparticles have the capability to reverse multidrug resistance a major problem in chemotherapy.

2. THE EVOLUTION OF NANOTECHNOLOGY:

The Nanoscale was initially used by R. P. Feynman, a physicist. In his talk, 1959, called “There’s plenty of room at the bottom. But there’s not that much room - to put every atom in its place - the vision articulated by some nanotechnologists - would require magic fingers”. He was one of the first people to suggest that scaling down to nano level and starting from the bottom was the key to future technology and advancement.^7-8In ancient Greek ‘Nano’ means dwarf.⁹ Nanotechnology is the creation and utilization of materials, devices, and systems through the control of matter on the nanometre-length scale, i.e. at the level of atoms, molecules, and supramolecular structures. These technologies have been applied to improve drug delivery and to overcome some of the problems of drug delivery for cancer treatment. Several nanobiotechnologies mostly based on nanoparticles, have been used to facilitate drug delivery in cancer. The magic of nanoparticles mesmerize everyone because of their multifunctional character and they have given us hope for the recovery from this disease. Although we are practicing better drug delivery paths into the body, we ultimately seek more accurate protocols to eradicate cancer from our society. This review focuses on progress in treatment of cancer through delivery of anticancer agents via nanoparticles. In addition, it pays attention to development of different types of nanoparticles for cancer drug delivery.¹⁰

3. TYPES OF BIOMEDICAL NANOPARTICLES:

Although the number of different type of nanoparticles is increasing rapidly, most can be classified into two major types. Particles that contain organic molecules as a major building material and those that use inorganic elements, usually metals, as a core. Liposome, dendrimers, carbon nanotubes, emulsions, and other polymers are a large and well-established group of organic particles. Use of these organic nanoparticles has already produced exciting results.¹¹ Liposomes are being used as vehicles for drug delivery in different human tumors, including breast cancer. Dendrimers, used in MRI as contrast agents, have aided visualisation of various pathological processes. Conjugated with pharmacological agents and targeting molecules, organic nanovectors are potent vehicles for drug delivery and selective imaging of different human cancers. Most inorganic nanoparticles share the same basic structure. This consists of a central core that defines the fluorescence, optical, magnetic, and electronic properties of the particle, with a protective organic coating on the surface. This outside layer protects the core from degradation in a physiologically aggressive environment and can form electrostatic or covalent bonds, or both, with positively charged agents and biomolecules that have basic functional groups such as amines and thiols. Several research groups have successfully linked fluorescent nanoparticles to peptides, proteins, and oligonucleotides.

3.1 Multifunctional Nanoparticles:

Nanoparticles have a further advantage over larger microparticles, because they are better suited for intravenous delivery. The smallest capillaries in the body are 5–6 mm in diameter. The size of particles being distributed into the bloodstream must be significantly smaller than 5 mm, without forming aggregates, to ensure that the particles do not form an embolism. Nanoparticles can be used to deliver hydrophilic drugs, hydrophobic drugs, proteins, vaccines, biological macromolecules, etc. They can be formulated for targeted delivery to the lymphatic system, brain, arterial walls, lungs, liver, spleen, or made for long-term systemic circulation. Therefore, numerous protocols exist for synthesizing nanoparticles based on the type of drug used and the desired delivery route. Once a protocol is chosen, the parameters must be tailored to create the best possible characteristics for the nanoparticles.

Four of the most important characteristics of nanoparticles are their size, encapsulation efficiency, zeta potential (surface charge), and release characteristics. Different nanoparticles have been discussed below.

3.2 Lipid/Polymer Nanoparticles:

Positively charged lipid-based nanoparticles are known to trigger strong immune responses when injected into the body. This can be problematic when attempting to use this type of nanoparticle as a drug delivery vehicle. Lipid-based cationic nanoparticles are a new promising option for tumor therapy, because they display enhanced binding and uptake at the neo-angiogenic endothelial cells, which a tumor needs for its nutrition and growth.¹² By loading suitable cytotoxic compounds to the cationic carrier, the tumor endothelial and consequently also the tumor itself can be destroyed. For the development of such novel anti-tumor agents, the control of drug loading and drug release from the carrier matrix is essential. Structural investigation of drug/lipid membranes may give valuable information about the organization of drugs in lipid matrices. Screening of different matrices for a given drug may be useful for fast and efficient optimization of drug/lipid combinations in pharmaceutical development. In a new therapeutic approach, targeted drug delivery is performed not to the tumor itself, but to the neo-angiogenic blood vessels that the tumor stimulates to grow for its nutrition. This procedure is based on the observation that cationic liposomes show enhanced binding and uptake at tumor endothelial cells. For efficient development of pharmaceutical formulations, it is useful to obtain an insight into the physico-chemical constraints of drug loading and drug release from the lipid matrix. Structural investigation of drug/lipid membranes, for example by X-ray scattering techniques, can give valuable information about the organization of a drug in the membrane, and it can help to optimize a lipid matrix with respect to its solubilizing potency of a given drug. Polymeric nanoparticle, are stable and non-phototoxic upon systemic administration. Upon cellular internalization, the photosensitizer is released from the nanoparticle and becomes highly phototoxic. Irradiation with visible light results in cell-specific killing of several cancer cell lines.¹³

3.3 Gold / Magnetic Nanoparticles:

As the distance increases, the number of particles decreases, revealing a particle gradient. Bottom: Simplified representation of the material showing particles in decreasing concentration along the surface.

Gold nanoparticles are the most commonly used nanoparticles for diagnostics and drug delivery. The unique chemical properties of colloidal gold make it a promising targeted delivery approach for drugs or gene specific cells. Gold and silica composite nanoparticles have been investigated as nanobullets for cancer.^14-15 The use of magnetic nanoparticles in cell biology was first proposed in the early 1990s, and their use has made the separation of cells or molecules such as proteins, peptides and DNA considerably easier.¹⁶ In medicine, nanoparticles first found use in the diagnosis of tumors in the liver and spleen using magnetic resonance tomography. In cancer therapy a major difficulty is to destroy tumor cells without harming the normal tissue. Radiotherapy attempts to focus irradiation on the tumor, but nevertheless damages healthy tissue which cannot always be protected in the desired way. Magnetic drug targeting employing nanoparticles as the carrier is a promising cancer treatment avoiding side effects of conventional chemotherapy.¹⁷ There is also a very significant role of hyperthermia in cancer drug delivery. There is increasing evidence that hyperthermia at 40–43°C enhances the uptake of therapeutic agents into cancer cells and provides an opportunity for improved targeted drug delivery. Using nanoparticles (NPs) for drug delivery of anticancer agents has significant advantages such as the ability to target specific locations in the body, the reduction of the overall quantity of drug used, and the potential to reduce the concentration of the drug at non target sites resulting in fewer unpleasant side effects.^18-19

3.4 Virus Based Nanoparticles:

In the latest research development virus-based nanoparticles are being extensively investigated for nanobiotechnology application.^20-23 Viruses have long been envisaged as nanoparticle vectors suitable for drug delivery, vaccines, and gene therapy. Recently, viruses have been explored as nano-containers for specific targeting applications. However these systems typically require modification of the virus surface using chemical or genetic means to achieve tumor-specific delivery. The latest technology developed engineered virus (nanoparticles) for cancer treatment. Viruses by their extraordinarily nature are well-defined nanoparticles, and several teams of investigators are taking a cue from nature and developing non-infectious, engineered viral nanoparticles for use as multifunctional nanoscale devices.

4. PREPARATION OF NANOPARTICLES:

Nanoparticles can be prepared from a variety of materials such as proteins, polysaccharides and synthetic polymers. The selection of matrix materials is dependent on many factors including size of nanoparticles required, inherent properties of the drug, e.g., aqueous solubility and stability, surface characteristics such as charge and permeability, degree of biodegradability, biocompatibility and toxicity, drug release profile desired and antigenicity of the final product.²⁴ Nanoparticles have been prepared most frequency by three methods first dispersion of preformed polymers, second polymerization of monomers and third ionic gelation or coacervation of hydrophilic polymers. However, other methods such as supercritical fluid technologyand particle replication in non-wetting templateshave also been described in the literature for production of nanoparticles.^25-26 The latter was claimed to have absolute control of particle size, shape and composition, which could set an example for the future mass production of nanoparticles in industry.

4.1 Dispersion of preformed polymers:

Dispersion of preformed polymers is a common technique used to prepare biodegradable nanoparticles from poly (lactic acid) (PLA); poly (D,L-glycolide), PLG; poly (D, L-lactide-co-glycolide) (PLGA) and poly (cyanoacrylate) (PCA).^27-29This technique can be used in various ways as described below.

4.1.1 Solvent evaporation method:

In this method, the polymer is dissolved in an organic solvent such as dichloromethane, chloroform or ethyl acetate which is also used as the solvent for dissolving the hydrophobic drug. The mixture of polymer and drug solution is then emulsified in an aqueous solution containing a surfactant or emulsifying agent to form an oil in water (o/w) emulsion. After the formation of stable emulsion, the organic solvent is evaporated either by reducing the pressure or by continuous stirring. Particle size was found to be influenced by the type and concentrations of stabilizer, homogenizer speed and polymer concentration.³⁰ In order to produce small particle size, often a high-speed homogenization or ultrasonication may be employed.³¹

4.1.2 Spontaneous emulsification or solvent diffusion method:

This is a modified version of solvent evaporation method.³²In this method, the water miscible solvent along with a small amount of the water immiscible organic solvent is used as an oil phase. Due to the spontaneous diffusion of solvents an interfacial turbulence is created between the two phases leading to the formation of small particles. As the concentration of water miscible solvent increases, a decrease in the size of particle can be achieved. Both solvent evaporation and solvent diffusion methods can be used for hydrophobic or hydrophilic drugs. In the case of hydrophilic drug, a multiple w/o/w emulsion needs to be formed with the drug dissolved in the internal aqueous phase.

4.2 Polymerization method:

In this method, monomers are polymerized to form nanoparticles in an aqueous solution. Drug is incorporated either by being dissolved in the polymerization medium or by adsorption onto the Nanoparticles after polymerization completed. The nanoparticle suspension is then purified to remove various stabilizers and surfactants employed for polymerization by ultracentrifugation and re-suspending the particles in an isotonic surfactant-free medium. This technique has been reported for making polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles.^33-34 Nanocapsule formation and their particle size depend on the concentration of the surfactants and stabilizers used.³⁵

4.3 Coacervation or ionic gelation method:

Much research has been focused on the preparation of nanoparticles using biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate. Calvo and co-workers developed a method for preparing hydrophilic chitosan nanoparticles by ionic gelation.^36-37 The method involves a mixture of two aqueous phases, of which one is the polymer chitosan, a di-block co-polymer ethylene oxide or propylene oxide (PEO-PPO) and the other is a polyanion sodium tripolyphosphate. In this method, positively charged amino group of chitosan interacts with negative charged tripolyphosphate to form coacervates with a size in the range of nanometer. Coacervates are formed as a result of electrostatic interaction between two aqueous phases, whereas, ionic gelation involves the material undergoing transition from liquid to gel due to ionic interaction conditions at room temperature.

4.4 Chemical solution method:

Conventional methods such as solvent extraction-evaporation, solvent diffusion and organic phase separation methods require the use of organic solvents which are hazardous to the environment as well as to physiological systems. Therefore, the supercritical fluid technology has been investigated as an alternative to prepare biodegradable micro- and nanoparticles because supercritical fluids are environmentally safe.³⁸ A supercritical fluid can be generally defined as a solvent at a temperature above its critical temperature, at which the fluid remains a single phase regardless of pressure. Supercritical CO2 (SC CO2) is the most widely used supercritical fluid because of its mild critical conditions (Tc = 31.1 °C, Pc = 73.8 bars), nontoxicity, non-flammability, and low price. The most common processing techniques involving supercritical fluids are supercritical anti-solvent (SAS) and rapid expansion of critical solution (RESS). The process of SAS employs a liquid solvent, eg methanol, which is completely miscible with the supercritical fluid (SC CO2), to dissolve the solute to be micronized; at the process conditions, because the solute is insoluble in the supercritical fluid, the extract of the liquid solvent by supercritical fluid leads to the instantaneous precipitation of the solute, resulting the formation of nanoparticles. RESS differs from the SAS process in that its solute is dissolved in a supercritical fluid (such as supercritical methanol) and then the solution is rapidly expanded through a small nozzle into a region lower pressure, Thus the solvent power of supercritical fluids dramatically decreases and the solute eventually precipitates. This technique is clean because the precipitate is basically solvent free. RESS and its modified process have been used for the product of polymeric nanoparticles.³⁹ Supercritical fluid technology technique, although environmentally friendly and suitable for mass production, requires specially designed equipment and is more expensive.

5. CHARACTERISATION OF NANOPARTICLE:

5.1 Particle size:

Particle size and size distribution are the most important characteristics of nanoparticle systems. They determine the in vivo distribution, biological fate, toxicity and the targeting ability of nanoparticle systems. In addition, they can also influence the drug loading, drug release and stability of nanoparticles. Many studies have demonstrated that nanoparticles of sub-micron size have a number of advantages over microparticles as a drug delivery system.⁴⁰

5.2 Surface properties of nanoparticles:

Nanomaterials exibihit some remarkable specific properties that may be significantly different from the physical properties of bulk materials. Some known physical properties of nanomaterials are related to different origins; for example, large fraction of surface atoms, large surface energy, spatial confinement, and reduced imperfections. The followings are the Some of the examples are discussed here like. Nanomaterials may have a significantly lower melting point or phase transition temperature and appreciably reduced lattice constants, due to huge fraction of surface atoms. Mechanical properties of nanomaterials may reach the theoretical strength, which are one of two orders of magnitude higher than that of single crystals in the bulk form. Optical properties of nanomaterials can be significantly different from bulk crystals. Electrical conductivity decrease with a reduced dimension due to increased surface scattering. Magnetic properties of nanostructured materials are distinctly different from that of bulk materials. Self-purification is an intrinsic thermodynamic property of nanostructures and nanomaterials.

6. NANOPARTICLES DRUG DELIVERY SYSTEM:

6.1 Drug loading:

Ideally, a successful nanoparticulate system should have a high drug-loading capacity thereby reduce the quantity of matrix materials for administration. Drug loading can be done by two methods like Incorporating at the time of nanoparticles production and absorbing the drug after formation of nanoparticles by incubating the carrier with a concentrated drug solution (adsorption /absorption technique). Different proteins compete to bind the nanoparticles and green florescent proteins, giving characteristic florescence profiles.

Drug loading and entrapment efficiency very much depend on the solid-state drug solubility in matrix material or polymer (solid dissolution or dispersion), which is related to the polymer composition, the molecular weight, the drug polymer interaction and the presence of end functional groups (ester or carboxyl).^41-43 The PEG moiety has no or little effect on drug loading.[44] The macromolecule or protein shows greatest loading efficiency when it is loaded at or near its isoelectric point when it has minimum solubility and maximum adsorption. For small molecules, studies show the use of ionic interaction between the drug and matrix materials can be a very effective way to increase the drug loading.^45-46

6.2 Drug release:

To develop a successful nanoparticulate system, both drug release and polymer biodegradation are important consideration factors. In general, drug release rate depends on solubility of drug; desorption of the surface bound/ adsorbed drug; drug diffusion through the nanoparticle matrix; nanoparticle matrix erosion/degradation; and combination of erosion/diffusion process. The image below is of drug delivering nanoparticles.

Thus solubility, diffusion and biodegradation of the matrix materials govern the release process. In the case of nanospheres, where the drug is uniformly distributed, the release occurs by diffusion or erosion of the matrix under sink conditions. If the diffusion of the drug is faster than matrix erosion, the mechanism of release is largely controlled by a diffusion process. The rapid initial release or ‘burst’ is mainly attributed to weakly bound or adsorbed drug to the large surface of nanoparticles.⁴⁷ It is evident that the method of incorporation has an effect on release profile. If the drug is loaded by incorporation method, the system has a relatively small burst effect and better sustained release characteristics.⁴⁸

6.3 Drug Delivery Strategies Used to Fight Cancers:

There are a variety of different delivery strategies that are either currently being used or are in the testing stage to treat human cancers as follows.⁴⁹

Direct introduction of anticancer drugs into tumor: Injection directly into the tumors, Tumors neurosis therapy, Injection into the arterial blood supply of cancer, Local injection into the tumor for radiopotention, Localized delivery of anticancer by inplants.

Routes of delivery: Intraperitoneal, Intrathecal, Nasal, Oral, Pulmonary inhalation, Subcutaneous injection or implants, Transdermal drug delivery, Vascular routes : intravenous, intra-arterial.

Systematic delivery targeted to tumor: Heat activated targeted drug delivery, Tissue selective drug delivery for cancer using carriers-mediated transport system, Tumor-activated prodrug therapy for targeted delivery of chemocherapy, Pressure induced filteration of drug across vessels to tumors, Promoting selective permeation of the anticancer agent into the tumor, Two-step targeting using bispecific antibody, Site specific delivery and light activation.

Drug delivery targeted to blood vessels of tumors: Antiangiogenesis therapy, Aangiolytic therapy, Drugs to induce clloting in blood vessels of tumors, Vascular targeting agents.

Special formulations and carriers of anticancer drugs: Albumin based drugs carriers, Carbohydrate enhanced chemotherapy, Delivery of proteins and peptides for cancer therapy, Fatty acid as targeting vectors linked to active drugs , Microspheres, Monoclonal antibodies Peglycated liposomes (enclosed polyethylene glycol bilayer), Polyethylene glycol (PEG)technology, Single-chain antigen binding technology.

Transmembrane drug delivery to intracellular tangents: Cytoporter, Receptor-mediated endocydosis, Transduction of proteins and peptides, Vitamins as carriers of anticancer agents.

Biological therapies: Antisense therapy, Cell therapy, Gene therapy, Genetically modified bacteria, Oncolytic viruses.

6.4 Pathways of Nanoparticles in Cancer Drug Delivery

Nanotechnology has tremendous potential to make an important contribution in cancer prevention, detection, diagnosis, imaging and treatment. It can target a tumor, carry imaging capability to document the presence of tumor, sense pathophysiological defects in tumor cells, deliver therapeutic genes or drugs based on tumor characteristics, respond to external triggers to release the agent and document the tumor response and identify residual tumor cells. Nanoparticles are important because of their nanoscaled structure but nanoparticles in cancer are still bigger than many anticancer drugs. Their “large” size can make it difficult for them to evade organs such as the liver, spleen, and lungs, which are constantly clearing foreign materials from the body. In addition, they must be able to take advantage of subtle differences in cells to distinguish between normal and cancerous tissues. Indeed, it is only recently that researchers have begun to successfully engineer nanoparticles that can effectively evade the immune system and actively target tumors. Active tumor targeting of nanoparticles involves attaching molecules, known collectively as ligands to the outsides of nanoparticles.⁵⁰

7. APPLICATIONS OF NANOPARTICULATE DELIVERY SYSTEM:

7.1 Tumor targeting using nanoparticulate delivery systems:

The rationale of using nanoparticles for tumor targeting is based on nanoparticles will be able to deliver a concentrate dose of drug in the vicinity of the tumor targets via the enhanced permeability and retention effect or active targeting by ligands on the surface of nanoparticles and nanoparticles will reduce the drug exposure of health tissues by limiting drug distribution to target organ. Studies show that the polymeric composition of nanoparticles such as type, hydrophobicity and biodegradation profile of the polymer along with the associated drug’s molecular weight, its localization in the nanospheres and mode of incorporation technique, adsorption or incorporation, have a great influence on the drug distribution pattern in vivo. The exact underlying mechanism is not fully understood but the biodistribution of nanoparticles is rapid, within ½ hour to 3 hours, and it likely involves MPS and endocytosis/phagocytosis process.⁵¹ This indicates the greatest challenge of using nanoparticles for tumour targeting is to avoid particle uptake by mononuclear phagocytic system (MPS) in liver and spleen. Such propensity of MPS for endocytosis/phagocytosis of nanoparticles provides an opportunity to effectively deliver therapeutic agents to these cells. This biodistribution can be of benefit for the chemotherapeutic treatment of MPS- rich organs/tissues localized tumors like hepatocarcinoma, hepatic metastasis arising from digestive tract or gynecological cancers brochopulmonary tumors, primitive tumors and metastasis, small cell tumors, myeloma and leukemia. It has been proved that using doxorubicin loaded conventional nanoparticles was effective against hepatic metastasis model in mice. It was found there was greater reduction in the degree of metastasis than when free drug was used. The underlying mechanism for the increased therapeutic efficacy of the formulation was transfer of doxorubicin from healthy tissue, acting as a drug reservoir to the malignant tissue.⁵²

7.2 Long circulating nanoparticles:

To be successful as a drug delivery system, nanoparticles must be able to target tumors which are localized outside MPS-rich organs. In the past decade, a great deal of work has been devoted to developing so-called “stealth” particles or PEGylated nanoparticles, which are invisible to macrophages or phagocytes.⁵³ A major breakthrough in the field came when the use of hydrophilic polymers (such as polyethylene glycol, poloxamines, poloxamers, and polysaccharides) to efficiently coat conventional nanoparticle surface produced an opposing effect to the uptake by the MPS.⁵⁴ These coatings provide a dynamic “cloud” of hydrophilic and neutral chains at the particle surface which repel plasma proteins.^55-56 As a result, those coated nanoparticles become invisible to MPS, therefore, remained in the circulation for a longer period of time. Hydrophilic polymers can be introduced at the surface in two ways, either by adsorption of surfactants or by use of block or branched copolymers for production of nanoparticles. As a result, such long-circulating nanoparticles have increased the potential to directly target tumors located outside MPS-rich regions. Coating conventional nanoparticles with surfactants or PEG to obtain a long-circulating carrier has now been used as a standard strategy for drug targeting in vivo.

7.3 Reversion of multidrug resistance in tumour cells:

Anticancer drugs, even if they are located in the tumour interstitium, can turn out to be of limited efficacy against numerous solid tumour types, because cancer cells are able to develop mechanisms of resistance.⁵⁷ These mechanisms allow tumours to evade chemotherapy. Multidrug resistance (MDR) is one of the most serious problems in chemotherapy. MDR occurs mainly due to the over expression of the plasma membrane pglycoprotein (Pgp), which is capable of extruding various positively charged xenobiotics, including some anticancer drugs, out of cells. In order to restore the tumoral cells’ sensitivity to anticancer drugs by circumventing Pgp-mediated MDR, several strategies including the use of colloidal carriers have been applied. The rationale behind the association of drugs with colloidal carriers, such as nanoparticles, against drug resistance derives from the fact that Pgp probably recognizes the drug to be effluxed out of the tumoral cells only when this drug is present in the plasma membrane, and not when it is located in the cytoplasm or lysosomes after endocytosis.^58-59

7.4 Nanoparticles for oral delivery of peptides and proteins:

Significant advances in biotechnology and biochemistry have led to the discovery of a large number of bioactive molecules and vaccines based on peptides and proteins. Development of suitable carriers remains a challenge due to the fact that bioavailability of these molecules is limited by the epithelial barriers of the gastrointestinal tract and their susceptibility to gastrointestinal degradation by digestive enzymes. Polymeric nanoparticles allow encapsulation of bioactive molecules and protect them against enzymatic and hydrolytic degradation. For instance, it has been found that insulin-loaded nanoparticles have preserved insulin activity and produced blood glucose reduction in diabetic rats for up to 14 days following the oral administration.⁶⁰ The surface area of human mucosa extends to 200 times that of skin.⁶¹ The gastrointestinal tract provides a variety of physiological and morphological barriers against protein or peptide delivery, e.g., (a) proteolytic enzymes in the gut lumen like pepsin, trypsin and chymotrypsin; (b) proteolytic enzymes at the brush border membrane (endopeptidases); (c) bacterial gut flora; and (d) mucus layer and epithelial cell lining itself.⁶² One important strategy to overcome the gastrointestinal barrier is to deliver the drug in a colloidal carrier system, such as nanoparticles, which is capable of enhancing the interaction mechanisms of the drug delivery system and the epithelia cells in the GI tract. .

7.5 Targeting of nanoparticles to epithelial cells in the GI tract using ligands:

Targeting strategies to improve the interaction of nanoparticles with adsorptive enterocytes and M-cells of Peyer’s patches in the GI tract can be classified into those utilizing specific binding to ligands or receptors and those based on nonspecific adsorptive mechanism. The surface of enterocytes and M cells display cell-specific carbohydrates, which may serve as binding sites to colloidal drug carriers containing appropriate ligands. Certain glycoproteins and lectins bind selectively to this type of surface structure by specific receptor-mediated mechanism. Different lectins, such as bean lectin and tomato lectin, have been studied to enhance oral peptide adsorption.^63-64 Vitamin B-12 absorption from the gut under physiological conditions occurs via receptor-mediated endocytosis. The ability to increase oral bioavailability of various peptides (e.g., granulocyte colony stimulating factor, erythropoietin) and particles by covalent coupling to vitamin B-12 has been studied.^65-66 For this intrinsic process, mucoprotein is prepared by the mucus membrane in the stomach and binds specifically to cobalamin. The mucoprotein completely reaches the ileum where resorption is mediated by specific receptors.

7.6 Nanoparticles for gene delivery:

Polynucleotide vaccines work by delivering genes encoding relevant antigens to host cells where they are expressed, producing the antigenic protein within the vicinity of professional antigen presenting cells to initiate immune response. Such vaccines produce both humoral and cell-mediated immunity because intracellular production of protein, as opposed to extracellular deposition, stimulates both arms of the immune system.⁶⁷ The key ingredient of polynucleotide vaccines, DNA, can be produced cheaply and has much better storage and handling properties than the ingredients of the majority of protein-based vaccines. Hence, polynucleotide vaccines are set to supersede many conventional vaccines particularly for immunotherapy. Nanoparticles loaded with plasmid DNA could also serve as an efficient sustained release gene delivery system due to their rapid escape from the degradative endo-lysosomal compartment to the cytoplasmic compartment.⁶⁸

7.7 Nanoparticles for drug delivery into the brain:

The blood-brain barrier (BBB) is the most important factor limiting the development of new drugs for the central nervous system. The BBB is characterized by relatively impermeable endothelial cells with tight junctions, enzymatic activity and active efflux transport systems. It effectively prevents the passage of water-soluble molecules from the blood circulation into the CNS, and can also reduce the brain concentration of lipid-soluble molecules by the function of enzymes or efflux pumps.⁶⁹ Consequently, the BBB only permits selective transport of molecules that are essential for brain function. Strategies for nanoparticle targeting to the brain on the presence of and nanoparticle interaction with specific receptor-mediated transport systems in the BBB. For example polysorbate 80/LDL, transferrin receptor binding antibody (such as OX26), lactoferrin, cell penetrating peptides and melanotransferrin have been shown capable of delivery of a self non transportable drug into the brain via the chimeric construct that can undergo receptor-mediated transcytosis.^70-74 It has been reported poly (butylcyanoacrylate) nanoparticles was able to deliver hexapeptide dalargin, doxorubicin and other agents into the brain which is significant because of the great difficulty for drugs to cross the BBB. Despite some reported success with polysorbate 80 coated NPs, this system does have many shortcomings including desorption of polysorbate coating, rapid NP degradation and toxicity caused by presence of high concentration of polysorbate-80.⁷⁵ OX26 MAbs (anti-transferrin receptor MAbs), the most studied BBB targeting antibody, have been used to enhance the BBB penetration of liposome.⁷⁶

7.8 Delivery of specific anticancer drugs as nanoparticles:

Paclitaxel: Biodegradable nanoparticles formulation using poly (lactic-co-glycolic) acid has shown comparable activity to traditional formulation and much faster administration .paclitaxel could be incorporated at very high loading efficiencies nearing 100% using nanoprecipitation method which leads to a very narrow therapeutic index.^77-78

Doxorubicin: Doxorubicin has a number of undesirable side effects, such as cardio toxicity and myelosuppression, which leads to a very narrow therapeutic index. Conjugates of dextran and doxorubicin have been encapsulated in chitosan nanoparticles of approximately 100nm diameter and it was found to cure tumor injected mice by 60%.Conjugated doxorubicin to PLGA nanoparticles showed an in vitro.⁷⁹

5-Fluorouracil: The hydrophillicity of 5-fluorouracil (5-FU) allowed it to complex with dendrimers after simply incubating the polymer with the drug. The dendrimer formulation showed 5-FU clearance only after 7h for non-PEG-ylated system and 13h for PEG-ylated system, which shows ability to control the 5-FU release in vivo and the extension of that release by PEG ylations of the polymers in the formulations.⁸⁰

8. CONCLUSION:

Nanotechnology is definitely a medical boon for diagnosis, treatment and prevention of cancer disease. It will radically change the way we diagnose, treat and prevent cancer to help meet the goal of eliminating suffering and death from cancer. Although most of the technologies described are promising and fit well with the current methods of treatment, there is still safety concerns associated with the introduction of nanoparticles in the human body. These will require further studies before some of the products can be approved. The most promising methods of drug delivery in cancer will be those that combine diagnostics with treatment. These will enable personalized management of cancer and provide an integrated protocol for diagnosis and follow up that is so important in management of cancer patients. There are still many advances needed to improve nanoparticles for treatment of cancers. Future efforts will focus on identifying the mechanism and location of action for the vector and determining the general applicability of the vector to treat all stages of tumors in preclinical models. Further studies are focused on expanding the selection of drugs to deliver novel nanoparticle vectors. Hopefully, this will allow the development of innovative new strategies for cancer cures.

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Received on 10.01.2011

Accepted on 17.01.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(2): March-April 2011, 33-41