Table of content

1. Abstract.....1 2. Introduction......1 3. Problems of Conventional chemotherapeutic agents........................2 4. Goals and specifications of targeted nanoscale drug delivery system..2 5. The delivery of the drug to the target tissue can be achieved primarily in two ways passive and active.2 5.1. Passive Targeting.2 5.2. Active Targeting..4 6. Types of Nanoparticles Used as Drug Delivery systems 5 6.1. Polymer-based drug carriers ...6 6.1.1. Polymeric nanoparticles (polymer-drug conjugates)..6 6.1.2. Polymeric micelles (amphiphilic block copolymers).....7 6.1.3. Dendrimers.....9 6.2. Lipid-based drug carriers (liposome)..9 6.3. Viruses (Viral nanoparticles).11 6.4. Carbon nanotubes..12 6.5. Others13 6.5.1. Nanospheres..13 6.5.2. Nanocapsules13 6.5.3. pH-Sensitive Carriers...14 6.5.4. Nucleic acid based nanoparticles (DNA, RNA and ASO).15 7. Nanoparticles in clinical use...15 7.1. Liposomal anthracyclines..16 7.1.1. Pegylated liposomal doxorubicin (Doxil) 16 7.1.2. Pegylated daunorubicin (DaunoXome)17 7.2. Nanoparticle-albumin conjugate nab-paclitaxel (Abraxane).17 7.3. Docetaxel encapsulated nanoparticle aptamer bioconjugate.19 8. Conclusion..20
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List of figures
1. Figure 1. Passive targeting of nanocarriers...4 2. Figure 2. Active targeting strategies.5 3. Figure 3.Polymeric micelle...7 4. Figure 4. Dendrimers.9 5. Figure 5. Liposome9 6. Figure 6. Carbon nanotube..12 7. Figure 7. Nanosphere .13 8. Figure 8. Nanocapsule.13 9. Figure.9 Schematic representation of pH-responsive nanocarriers.14

List of tables
1. Table 1: Some Examples of Liposomal Drugs Approved for Clinical Application or Undergoing Clinical Evaluation for Cancer Therapy11

List of abbreviation
EPR HPMA enhanced permeability and retention N-(2-hydroxy propyl)-methacrylamide copolymer PEG PGA HA ASO Si RNA PEI PAMAM PPI RES PSMA LNCAP poly ethylene glycol poly-L- glutamic acid hyaluronic acid anti sense oligonucleotides small interfering RNA poly ethylen imine poly amido amine poly propylene imine reticuloendothelial system prostate specic membrane antigen androgen sensitive human prostate adencarcinoma cells

PLGA-b-PEG poly (D, L- lacti - co- glycolic acid) block - poly ethylene glycol
4

1. Abstract
Nanocarriers is new approach in drug delivery system that enhance properties of the drugs such as improve pharmacokinetics and pharmacodynamics , improve solubility and targeting of the drugs to specific tissue ,so overcome the problems of conventional chemotherapeutic agents . this report discus types of nanocarriers and their clinical applications

2. Introduction
Cancer is essentially a genetic disease characterized by increased cellular proliferation, reduced cell death, or usually a combination of both. At the molecular level, multiple subsets of genes undergo alterations, either activation of oncogenes or inactivation of tumor suppressor genes, or in advanced disease, a combination of both. This results in rapid proliferation of cancer cells, reduced cell death, tissue infiltration, establishment of a blood supply to the tumor, metastasis to secondary sites in the body, and dysfunction of affected organs (Sarkar et al., 2007). The ultimate goal of cancer therapeutics is to increase the survival time and the quality of life of the patient by reducing the unintended harmful side-effects (Byrne et al., 2008). The most common cancer treatments are chemotherapy, radiation and surgery (Singhal et al., 2010), with chemotherapy being the major treatment modality. However, conventional chemotherapeutic agents are limited by their undesirable properties, such as poor solubility, narrow therapeutic window, and cytotoxicity to normal tissues, which may be the cause of treatment failure in cancer (Pulkkinen et al., 2008). Cancer nanotechnology is a new field of interdisciplinary research aiming to enhance methods for cancer diagnosis and treatment. Among the various approaches, nanocarriers (particularly in the size range from 10 to 100 nm) offer some unique properties such as high surface area to volume ratio and can be designed to carry therapeutic molecules that distinguish them from other cancer therapeutics (Wang et al., 2007). Nanocarriers are being trialed for target-specific delivery of drugs to cancer sites in the body in order to improve the therapeutic efficacy because of improved specificity, increased internalization and intracellular delivery while minimizing undesirable side-effects.
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3. Problems of Conventional chemotherapeutic agents

Conventional chemotherapeutic agents are distributed nonspecifically in the body where they affect both cancerous and normal cells, thereby limiting the dose achievable within the tumor and also resulting in suboptimal treatment due to excessive toxicities .Another limitations of chemotherapeutic agents including lack of water solubility, poor oral bioavailability, low therapeutic indices and multidrug resistance

4. Goals and specifications of targeted nanoscale drug delivery system

Increase drug concentration in the tumor through: (a) Passive targeting (b) Active targeting

Decrease drug concentration in normal tissue Improve phamacokinetics and pharmacodynamics profiles Improve the solubility of drug to allow intravenous administration Release a minimum of drug during transit Release a maximum of drug at the targeted site Increase drug stability to reduce drug degradation Improve internalization and intracellular delivery Biocompatible and biodegradable.
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5. The delivery of the drug to the target tissue can be achieved primarily in two ways passive and active
5.1. Passive Targeting Passive targeting consists in the transport of nanocarriers through leaky tumor capillary fenestrations into the tumor interstitium and cells by convection or passive diffusion (Fig. 1). The convection refers to the movement of molecules within uids. Convection must be the predominating transport mode for most large molecules across large pores when the net ltration rate is zero. In the contrary, low molecular weight compounds, such as oxygen, are mainly transported by diffusion, dened as a
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process of transport of molecules across the cell membrane, according to a gradient of concentration, and without contribution of cellular energy.

Nevertheless, convection through the tumor interstitium is poor due to interstitial hypertension, leaving diffusion as the major mode of drug transport. Selective accumulation of nanocarriers and drug then occurs by the EPR effect .The EPR effect is now becoming the gold standard in cancer-targeting drug designing. All nanocarriers use the EPR effect as a guiding principle. Moreover, for almost all rapidly growing solid tumors the EPR effect is applicable.

Indeed, EPR effect can be observed in almost all human cancers with the exception of hypovascular tumors such as prostate cancer or pancreatic cancer.The EPR effect will be optimal if nanocarriers can evade immune surveillance and circulate for a long period. Very high local concentrations of drug-loaded nanocarriers can be achieved at the tumor site, for instance 1050-fold higher than in normal tissue within 12 days. To this end, at least three properties of nanocarriers are particularly important.

(i) The ideal nanocarriers size should be somewhere between 10 and 100 nm. Indeed, for efcient extravasation from the fenestrations in leaky vasculature, nanocarriers should be much less than 400 nm. On the other hand, to avoid the ltration by the kidneys, nanocarriers need to be larger than01 nm; and to avoid the specic capture by the liver, nanocarriers need to be smaller than 100 nm. (ii) The charge of the particles should be neutral or anionic for efcient evasion of the renal elimination.

(iii) The nanocarriers must be hidden from the reticuloendothelial system, which destroys any foreign material through opsonization followed by phagocytosis Nevertheless, to reach passively the tumor, some limitations exist. (i) The passive targeting depends on the degree of tumor vascularization and angiogenesis. Thus extravasation of nanocarriers will vary with tumor types and anatomical sites. (ii) As previously mentioned, the high interstitial uid pressure of solid tumors avoids successful uptake and homogenous distribution of drugs in the tumor . The high interstitial uid pressure of tumors associated with the poor lymphatic drainage
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explain the size relationship with the EPR effect: larger and long-circulating nanocarriers (100 nm) are more retained in the tumor, whereas smaller molecules easily diffuse.
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Figure 1. Passive targeting of nanocarriers. (1) Nanocarriers reach tumors selectively through the leaky vasculature surrounding the tumors. (2) Schematic representation of the influence of the size for retention in the tumor tissue. Drugs alone diffuse freely in and out the tumor blood vessels because of their small size and thus their effective concentrations in the tumor decrease rapidly. By contrast, drug-loaded nanocarriers cannot diffuse back into the blood stream because of their large size, resulting in progressive accumulation: the EPR effect 5.2. Active targeting In active targeting, targeting ligands are attached at the surface of the nanocarrier for binding to appropriate receptors expressed at the target site. The ligand is chosen to bind to a receptor over expressed by tumor cells or tumor vasculature and not expressed by normal cells. Moreover, targeted receptors should be expressed homogeneously on all targeted cells. Targeting ligands are either monoclonal antibodies (mAbs) and antibody fragments or non antibody ligands (peptidic or not).
(2)

Figure 2. Active targeting strategies. Ligands grafted at the surface of nanocarriers bind to receptors (over)expressed by (1) cancer cells or (2) angiogenic endothelial cells.

6. Types of Nanoparticles Used as Drug Delivery systems

Nanoparticles applied as drug delivery systems are submicronsized particles (3-200 nm), devices, or systems that can be made using a variety of materials including polymers (polymeric nanoparticles, micelles, or dendrimers), lipids (liposomes), viruses (viral nanoparticles), and even organometallic compound.

These drug carriers as well as any other pharmaceutical nanocarriers can be surface modified by a variety of different moieties to impart them with certain properties and functionalities. These functionalities are expected to provide nanocarriers:

1- Prolonged circulation in the blood and ability to accumulate in various pathological areas (eg, solid tumors) via the EPR effect (protective polymeric coating with polyethylene glycol [PEG] is frequently used for this purpose)

2- The ability to specifically recognize and bind target tissues or cells via the surfaceattached specific ligand (monoclonal antibodies as well as their Fab fragments and some other moieties, eg, folate or transferrin, are used for this purpose)

3- The ability to respond to local stimuli characteristic of the pathological site by, for example, releasing an entrapped drug or specifically acting on cellular membranes under the+ abnormal pH or temperature in disease sites (this property could be provided by surface-attached pH- or temperature sensitive components).

4- The ability to penetrate inside cells by passing lysosomal degradation for efficient targeting of intracellular drug targets (for this purpose, the surface of nanocarriers is additionally modified by cell-penetrating peptides)

6.1. Polymer-based drug carriers

Depending on the method of preparation, the drug is either physically entrapped in or covalently bound to the polymer matrix. The resulting compounds may have the structure of capsules (polymeric nanoparticles), amphiphilic core/shell (polymeric micelles), or hyper branched macromolecules (dendrimers). Polymers used as drug conjugates can be divided into two groups of natural and synthetic polymers.

6.1.1. Polymeric nanoparticles (polymer-drug conjugates) Polymers such as albumin, chitosan, and heparin occur naturally and have been a material of choice for the delivery of oligonucleotides, DNA, and protein, as well as drugs. Recently, a nanoparticles formulation of paclitaxel, in which serum albumin is included as a carrier [nanometer-sized albumin bound paclitaxel (Abraxane), has been applied in the clinic for the treatment of metastatic breast cancer. Besides metastatic breast cancer, Abraxane has also been evaluated in clinical trials involving many other cancers including nonsmall-cell lung cancer (phase II trial) and advanced nonhematologic malignancies (phase I and pharmacokinetics trials).

Among synthetic polymers such as N-(2-hydroxypropyl) - methacrylamide copolymer (HPMA), polystyrene-maleic anhydride copolymer, polyethylene glycol (PEG), and poly-L-glutamic acid (PGA), PGA was the first biodegradable polymer to be used for conjugate synthesis. Several representative chemotherapeutics that are used widely in the clinic have been tested as conjugates with PGA in vitro and in vivo and showed encouraging abilities to circumvent the shortcomings of their free drug counterparts. HPMA and PEG are the most widely used nonbiodegradable synthetic polymers.

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6.1.2. Polymeric micelles (amphiphilic block copolymers). The development of drug nanocarriers for poorly soluble pharmaceuticals is an important task, particularly because large proportions of new drug candidates emerging from high throughput drug screening initiatives are water-insoluble, but there are some unresolved issues. The therapeutic application of hydrophobic, poorly water- soluble agents is associated with some serious problems, since low water solubility results in poor absorption and low bioavailability. Figure 3.Polymeric micelle In addition, drug aggregation upon intravenous administration of poorly soluble drugs might lead to such complications as embolism and local toxicity.

On the other hand, the hydrophobicity and low solubility in water appear to be intrinsic properties of many drugs, since it he drug molecule to penetrate a cell

membrane and reach important intracellular targets. To overcome the poor solubility of certain drugs, the use of various micelle forming surfactants in formulations of insoluble drugs is suggested. This is why micelles, including polymeric micelles, are another promising type of pharmaceutical carrier.

Micelles are colloidal dispersions with a particle size between 5 nm and 100 nm. An important property of micelles is their ability to increase the solubility and bioavailability of poorly soluble pharmaceuticals. The use of certain special amphiphilic molecules as micelle building blocks can also extend the blood half-life upon intravenous administration.
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Because of their small size (5-100 nm), micelles demonstrate spontaneous penetration into the interstitium in the body compartments with leaky vasculature (tumors and infarcts) by the EPR effect a form of selective delivery termed passive targeting. It has been repeatedly shown that micelle-incorporated anticancer drugs, such as adriamycin (see, eg, Kwon and Kataoka ) accumulate better in tumors than in non target tissues, thus minimizing undesired drug toxicity toward normal tissue. The hydrophobic core region serves as a reservoir for hydrophobic drugs, whereas the hydrophilic shell region stabilizes the hydrophobic core and renders the polymers
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water-soluble, making the particle an appropriate candidate for I.V administration. The drug can be loaded into a polymeric micelle in two ways: physical encapsulation or chemical covalent attachment.

Multifunctional polymeric micelles containing targeting ligands and imaging and therapeutic agents are being actively developed and will become the mainstream among several models of the micellar formulation in the near future. NK911 and SP1049C are both examples of micellar-based drugs currently in Phase-I and Phase-III stages of clinical trials respectively (Danson et al., 2004; Kabanov, 2006; Wang et al., 2008; Valle et al., 2010) (Table 1). NK105 and NC6004 are also both micellar-based drugs currently in either Phase- II or Phase-I/II stages of clinical trials (Hamaguchi et al., 2007; Wilson et al., 2008) (Table 1). While encouraging, all of these formulations passively deliver chemotherapeutics to cancer cells, and future work involves targeting ligand addition within these constructs. These ligands

include proteins (including antibodies), vitamins, as well as various carbohydrates (Nagasaki et al., 2001; Torchilin et al., 2003b;Licciardi et al., 2008). For example, immunomicelles containing a photosensitizing agent and tumor-specific monoclonal antibody have been successfully used in photodynamic therapy against murine lewis lung carcinoma (Roby et al., 2007).
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Micelles containing a folate moiety have been shown to be significantly more cytotoxic to ovarian carcinoma cells than non-targeted micelles (Kim et al., 2008). In fact, folate has also been successfully used recently as a targeting ligand in micelles to deliver poorly water-soluble chemotherapeutics (either tamoxifen or paclitaxol) to colon carcinoma cells (Licciardi et al., 2008). In addition, hyaluronic acid (HA)paclitaxel conjugate micelles have recently been shown to be far more cytotoxic toward HA receptor overexpressing cancer cells than for HA receptor deficient cells (Lee et al., 2008).
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6.1.3. Dendrimers

Dendrimer

is

synthetic

polymeric

macromolecule of nanometer dimensions, composed of multiple highly branched monomers that emerge radially from the central core. Properties associated with these dendrimers such as their

monodisperse size, modifiable surface functionality, multivalency, water

solubility, and available internal cavity make them attractive for drug delivery. Polyamidoamine dendrimer, the dendrimer most widely used as a scaffold, Figure 4. Dendrimers was conjugated with cisplatin. The easily modifiable surface characteristic of dendrimers enables them to be simultaneously conjugated with several molecules such as imaging contrast agents, targeting ligands, or therapeutic drugs, yielding a dendrimer-based multifunctional drug delivery system

6.2. Lipid-based drug carriers Liposome Liposomes are artificial phospholipids vesicles that vary in size from 50 to 1000 nm and can be loaded with a variety of water-soluble drugs (into their inner aqueous compartment) and sometimes even with water insoluble drugs (into the hydrophobic compartment of the phospholipid bilayer).

Figure 5. Liposome

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They are classified according to the number of lipid bilayers as either unilamellar or multilamellar. Unilamellar systems have an aqueous core for encapsulation of water soluble drugs, whereas multilamellar systems entrap lipid soluble drugs.
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They are biologically inert and completely biocompatible, and they cause practically no toxic or antigenic reactions; drugs included in liposomes are protected from the destructive action of external media. The use of targeted liposomes, that is, liposomes selectively accumulating inside an affected organ or tissue, increases the efficacy of the liposomal drug and decreases the loss of liposomes and their contents in the reticuloendothelial system (RES).To obtain targeted liposomes, many protocols have been developed to bind corresponding targeting moieties, including antibodies, to the liposome surface without affecting the liposome integrity and antibody properties.

For example, anti-HER2 immunoliposomes have been shown to be far more cytotoxic in HER2-overexpressing breast cancer cells than non-targeted liposomes (Gao et al., 2009). The cancer cell surface receptor CD44, which is found at elevated levels amongst various tumorigenic cells such as melanoma has also been the target of many liposomal-based strategies (Eliaz and Szoka, 2001; Rezler et al., 2007a.
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However, the approach with immunoliposomes may nevertheless be limited because of their short life in the circulation. Dramatically better accumulation can be achieved if the circulation time of liposomes is extended, increasing the total quantity of immunoliposomes passing through the target and increasing their interactions with target antigens. This is why long circulated (usually, coated with PEG, (ie, PEGylated) liposomes have attracted so much attention over the last decade. It was demonstrated that the unique properties of long circulating and targeted liposomes could be combined in 1 preparation in which antibodies or other specific binding molecules had been attached to the water-exposed tips of PEG chains. In any event, encapsulation of the drug serves to minimize the unintended side effects of commonly used chemotherapeutics in liposomal-formulations such as cardiotoxicity that generally results with the use of anthracyclines (i.e. doxorubicin) (Rivera, 2003), and peripheral neurotoxicity commonly associated with the use of both cisplatin and vincristine (Wang et al., 2000; Bianchi et al., 2006)

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Table 1. Some Examples of Liposomal Drugs Approved for Clinical Application or Undergoing Clinical Evaluation for Cancer Therapy
Active Drug (and product name for liposomal preparation) Daunorubicin (DaunoXome) Doxurubicin (Mycet) Doxorubicin in polyethylene glycol liposomes (Doxil, Caelyx) Vincristine (Onco TCS) Lurtotecan (NX211) Kaposi s sarcoma Combinational therapy of recurrent breast cancer Refractory Kaposi s sarcoma; ovarian cancer; recurrent breast cancer Non-Hodgkin s lymphoma Ovarian cancer Indications

Source: Vladimir P. Torchilin. (2007). Targeted Pharmaceutical Nanocarriers for Cancer Therapy and Imaging. American association of pharmaceutical scientists, 9 (2): E128-E147.

6.3. Viruses

Viral nanoparticles A variety of viruses including cowpea mosaic virus, cowpea chlorotic mottle virus, canine parvovirus, and bacteriophages have been developed for biomedical and nanotechnology applications that include tissue targeting and drug delivery. A number of targeting molecules and peptides can be displayed in a biologically functional form on their capsid surface using chemical or genetic means. Therefore, several ligands or antibodies including transferrin, folic acid, and single-chain antibodies have been conjugated to viruses for specific tumor targeting in vivo. Besides this artificial targeting, a subset of viruses, such as canine parvovirus, has natural affinity for receptors such as transferrin receptors that are up-regulated on a variety of tumor cells. By targeting heat shock protein, a dual-function protein cage with specific targeting and doxorubicin encapsulation has been developed.
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6.4. Carbon nanotubes Carbon nanotubes are carbon cylinders composed of benzene rings that have been applied in biology as sensors for detecting DNA and protein, diagnostic devices for the discrimination of different proteins from serum samples, and carriers to deliver vaccine or protein . Carbon nanotubes are completely insoluble in all solvents, generating some health concerns and toxicity problems. However, the introduction of chemical modification to

Figure 6. Carbon nanotube carbon nanotubes can render them water- soluble and functionalized so that they can be linked to a wide variety of active molecules such as peptides, proteins, nucleic acids, and therapeutic agents. Antifungal agents (amphotericin B) or anticancer drugs (methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent (FITC). In an in vitro study, drugs bound to carbon nanotubes were shown to be more effectively internalized into cells compared with free drug alone and to have potent antifungal activity. The multiple covalent functionalizations on the sidewall or tips of carbon nanotubes allow them to carry several molecules at once, and this strategy provides a fundamental advantage in the treatment of cancer.
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6.5. Others

6.5.1. Nanospheres These nanoparticles are spherical structures composed of a matrix system in which drug is distributed by entrapment, attachment, or

encapsulation. The surface of the sphere may be modified by the addition of polymers and biological materials like ligands or antibodies may also be attached for targeting purposes.
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Figure 7. Nanosphere

6.5.2. Nanocapsules These particles are vesicular systems with a central cavity or core to which a drug is confined. The core is surrounded by an outer shell polymeric membrane to which surface bound targeting ligands or antibodies may be attached. The core material may be solids, liquids, or gas, and the core environment may be aqueous or oily.
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Figure 8. Nanocapsule

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6.5.3. pH-Sensitive Carriers

PH-responsive nanocarriers can be constructed from stimuli responsive polymers that are able to sense small changes in microenvironmental pH which triggers a corresponding change in the polymer's physical properties such as size, shape or hydrophobicity. Drugs are encapsulated within these polymeric matrices. It is wellknown that tumor tissues have lower pH than normal tissues, thus antitumor drugs that are encapsulated or conjugated into carrier materials could be released rapidly in the acidic microenvironment of tumor tissues (Fig. 9). In order to improve the therapeutic effect of anticancer drugs that target the nucleus or other organelles or cytoskeletal structures after cellular uptake, the antitumor drug should be released rapidly from carrier
(1)

materials

in

the

acidic

microenvironment

of

endosomes/lysosomes.

Figure.9 Schematic representation of pH-responsive nanocarriers targeting.PHresponsive nanocarriers accumulate in the tumor tissue via the enhanced permeability and retention (EPR) effect through the leaky blood vessels. After pH-responsive nanocarriers accumulate in the tissue, the system is triggered to release the anticancer drug in response to pH stimuli, or is taken up by cancer cells after binding to target antigens on the surface of the cancer cells. In this latter case the drugs are released inside the cancer cells by pH in stimuli.

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6.5.4. Nucleic acid based nanoparticles (DNA, RNA and ASO)

Gene therapy refers to the direct transfer and expression of DNA into diseased cells for the therapeutic applications. Veiseh have developed a ligand mediated nanovector by binding the chlorotoxin (CTX) peptide and pegylation of DNAcomplexing polyethylenimine (PEI) in nanoparticles which functionalized with an Alexa Fluor 647 near infrared fluorophore. Mixed nanoparticles, prepared with generations 4 and 5 poly (amidoamine) (PAMAM) dendrimers and plasmid DNA, were confirmed to be effective for both in vitro and in vivo gene delivery to colon and liver cancer cells. Based on oligonucleotides, RNAi and ASO therapies can shut down the expression of target genes to treat the disease. Recently, siRNA nanoparticles were first designed with Poly (Propyleneimine) (PPI) dendrimers.
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7. Nanoparticles in clinical use

Despite extensive research and development, only a few drug delivery nanoparticles currently are FDA approved and available for cancer treatment. Liposomal anticancer drugs were the first to be approved for therapy in cancer. Two commercial liposomal formulations are available in the United States. These are pegylated liposomal doxorubicin (Doxil in the U.S. and Caelyx outside the U.S.) and liposomal daunorubicin (DaunoXome). A third liposomal formulation approved in Europe is nonpegylated liposomal doxorubicin (Myocet). Adding to this formulary, an albumin bound paclitaxel nanoparticle Abraxane was recently approved by the FDA for the treatment of breast cancer. The remaining parts of this discussion will focus on those nanoparticles approved and marketed for clinical oncology use.
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7.1. Liposomal anthracyclines

The available liposomal formulations represent encapsulated anthracyclines doxorubicin in Doxil and Myocet and daunorubicin in DaunoXome. While anthracyclines are highly active cytotoxic drugs, they have significant toxicity associated with their use both acute and cumulative. High peak plasma concentrations of anthracycline are associated with risk for congestive cardiomyopathy as is the lifetime cumulative dose of the drugs. By liposomal encapsulation, the anthracycline pharmacokinetics are altered and cardiac risk is decreased, but not eliminated [27,28]. Additionally, anthracycline toxicity to normal tissue, including alopecia and myelosuppression, are reduced by liposomal encapsulation.
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7.1.1. Pegylated liposomal doxorubicin (Doxil)

Doxil particles are small (100 nm) unilamellar vesicles with encapsulated doxorubicin

precipitated in the liposomal vesicle by an (NH4) SO4 gradient. The polyethylene glycol coating (pegylation) prevents opsonization and avoids RES clearance. It also adds steric stabilization to prolong the plasma t1/2. After extravasation through tumor endothelium,

Doxil liposomes disintegrate and deliver doxorubicin. Drug concentration has been measured at 10- fold higher in tumor tissue compared with conventional free drug administration. The recommended systemic dosage for Doxil is 40 to 50 mg/m2 infused over 1 hour every 4 weeks. The main toxicities are palmar plantar skin reactions (PPE) and stomatitis/mucositis. Compared with a conventional doxorubicin infusion, Doxil has less cardiotoxicity, myelosuppression, alopecia, nausea, and vomiting. The FDA approved three major indications for pegylated liposomal doxorubicinAIDS related Kaposis sarcoma, platinum pretreated ovarian cancer, and first line monotherapy of metastatic breast cancer.
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7.1.2. Pegylated daunorubicin (DaunoXome)

Due

to

the

relative

stability

of

daunorubicin in aqueous solution, the drug is encapsulated in a small unilamellar liposome (45 nm size). The NP has delayed opsonization and escapes rapid RES clearance resulting in a markedly to increased AUC

compared

conventionally

administered daunorubicin. The main toxicity observed for this drug is myelosuppression. The FDA approved indication for pegylated daunorubicin is for the treatment of Kaposis sarcoma. A Phase III trial randomized chemo nave Kaposis sarcoma patients to pegylated daunorubicin vs. a modified

adriamycin/bleomycin/vincristine (ABV) regimen. Overall response rates and median survival were not different between the two groups. Toxicities differed significantly with more grade 4 neutropenia for pegylated daunorubicin and greater alopecia and neuropathy for ABV.
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7.2. Nanoparticle-albumin conjugate nab-paclitaxel (Abraxane)

The taxanes are a family of tubulin stabilizing agents highly active and widely used in a variety of solid tumors including urologic malignancies. Paclitaxel and docetaxel are the commercially available taxanes for clinical treatment. Both of these drugs are hydrophobic and, due to solubility problems, are formulated with a solvent paclitaxel with Cremophor-EL and Tween-80 for docetaxel. These solvents can cause severe hypersensitivity reactions and toxicities. Due side effects. Patients must be premedicated with steroids and
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antihistamines prior to drug infusion. For paclitaxel, the drug must also be slowly infused over several hours. To decrease the toxic effects associated with these drugs, a nanoparticle formulation has been developed for paclitaxel. The technology for particle formation involves a proprietary process that binds unmodified albumin to the paclitaxel molecule yielding a nanoparticle of 130 nm size. After infusion, these particles rapidly dissociate to yield an albumin bound drug complex.

Albumin paclitaxel molecules bind to an albumin receptor (gp60) on endothelial cells that transports the hydrophobic paclitaxel into the extravascular space. The albumin receptors (gp60) cluster on endothelial surfaces and associate with caveolin-1, leading to the formation of a caveolae that is released into the extravascular space. Therefore, caveolae are a major transport mechanism for nab-paclitaxel. A second proposed transport pathway for the nanoparticles is via secreted protein acidic rich in cysteine (SPARC). Other names for this protein are BM40 and osteonectin. SPARC expression has been reported in many solid tumors including bladder and prostate cancers and is associated with a poor prognosis. SPARC protein can bind albumin and can increase the concentration of the albumin bound paclitaxel particle in the tumor due to such binding. Hence, SPARC protein represents another transport mechanism for nabpaclitaxel into tumor cells

Based on these properties, a nab-paclitaxel infusion leads to a 33% increase in intratumoral concentrations and a 50% higher dose of paclitaxel delivered compared with a conventional paclitaxel infusion; and, since nab-paclitaxel is solvent free, the infusion time is 30 minutes compared with the 3-hour infusion for conventional taxol, and no premedication is required. The FDA approved nab-paclitaxel for metastatic breast cancer therapy after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. A pivotal Phase III trial of 460 women compared nab-paclitaxel with conventional paclitaxel on a 3-week schedule. All patients were taxane nave. Overall response rates were significantly higher for nab-paclitaxel 33% vs. 19% and times to progression significantly longer 23 weeks for nab paclitaxel vs. 17 weeks. Overall survival was not significantly different for all patients. Toxicity profiles differed with nab-paclitaxel having less neutropenia compared to taxol but more grade 2 and 3 sensory neuropathy. To further explore issues of tolerance and dose response for this drug, a weekly infusional schedule has been studied and reported lower rates of neutropenia and neuropathy. All patients in this trial had
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previously been treated with paclitaxel, docetaxel, or both drugs, and were refractory. The observed response rates for the weekly nab-paclitaxel suggested that the drug was non-cross resistant for taxane refractory patients. This concept has particular implications for urologic cancers, notably prostate, a malignancy in which the only proven agent to prolong survival is a taxane. Nab-paclitaxel represents an alternative treatment option for such cancer patients treated with conventional taxanes who develop resistance or toxicity intolerance.
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7.3. Docetaxel encapsulated nanoparticle aptamer bioconjugate

This docetaxel encapsulated nanoparticle with the copolymer poly (D,L-lacti-co-glycolic acid) blockpoly (ethylene glycol) (PLGA-b-PEG) is surface targeted to the extracellular domain of prostate specific membrane antigen (PSMA) by the conjugation of an RNA aptamer. The aptamer binds to PSMA on the surface of LNCaP prostate epithelial cells and then is internalized into the cell. As a result, enhanced cellular toxicity is noted compared with the same NP lacking aptamers. Cell line and mouse xenograft studies of this molecule suggest great potential for therapeutic application in humans. The technology supporting the molecule design included utilizing biocompatible and biodegradable polymers with established safety for human use. The polymers allow sustained intracellular drug release. The RNA aptamer is an oligonucleotide capable of binding to the target antigen PSMA with high affinity and specificity. With the polymer coat, the NP escapes rapid RES clearance. Finally, the choice of docetaxel utilizes a cytotoxic drug already proven in clinical trials to prolong survival of (5) hormone resistant prostate cancer in humans.

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8. Conclusion
Nanotechnology is new area in research that provides several advantages for drug delivery systems especially for anticancer drugs. In the future this field will expand and involve new approach and strategies in tumor targeting, novel ligands, drug solubility and particle stabilization.

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