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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. Others………………………………………………………………13 6.5.1. Nanospheres………………………………………………………..13 6.5.2. Nanocapsules………………………………………………………13 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. Liposome………………………………………………………………………9 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

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Table 1: Some Examples of Liposomal Drugs Approved for Clinical Application or Undergoing Clinical Evaluation for Cancer Therapy………………………………………11 3 .List of tables 1.

poly ethylene glycol 4 .lacti .glycolic acid) block . L.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 specific membrane antigen androgen sensitive human prostate adencarcinoma cells PLGA-b-PEG poly (D.co.

The most common cancer treatments are chemotherapy. establishment of a blood supply to the tumor. multiple subsets of genes undergo alterations. and dysfunction of affected organs (Sarkar et al. reduced cell death. 2008). 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 ... or in advanced disease. However. this report discus types of nanocarriers and their clinical applications 2. such as poor solubility. At the molecular level. 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. narrow therapeutic window.. This results in rapid proliferation of cancer cells. 2007). a combination of both. tissue infiltration. 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. either activation of oncogenes or inactivation of tumor suppressor genes.1. 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. or usually a combination of both. increased internalization and intracellular delivery while minimizing undesirable side-effects. reduced cell death. 2007). 2010). which may be the cause of treatment failure in cancer (Pulkkinen et al. (1) 5 . conventional chemotherapeutic agents are limited by their undesirable properties.. radiation and surgery (Singhal et al. and cytotoxicity to normal tissues. metastasis to secondary sites in the body. Introduction Cancer is essentially a genetic disease characterized by increased cellular proliferation. 2008). Among the various approaches.. with chemotherapy being the major treatment modality. Cancer nanotechnology is a new field of interdisciplinary research aiming to enhance methods for cancer diagnosis and treatment.

In the contrary. 1). low molecular weight compounds. 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. The convection refers to the movement of molecules within fluids. thereby limiting the dose achievable within the tumor and also resulting in suboptimal treatment due to excessive toxicities . (2) 5. Problems of Conventional chemotherapeutic agents Conventional chemotherapeutic agents are distributed nonspecifically in the body where they affect both cancerous and normal cells. 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.Another limitations of chemotherapeutic agents including lack of water solubility. low therapeutic indices and multidrug resistance 4.3. defined as a 6 .1. Convection must be the predominating transport mode for most large molecules across large pores when the net filtration rate is zero. are mainly transported by diffusion. The delivery of the drug to the target tissue can be achieved primarily in two ways— passive and active 5. such as oxygen. poor oral bioavailability.

the high interstitial fluid pressure of solid tumors avoids successful uptake and homogenous distribution of drugs in the tumor . for instance 10–50-fold higher than in normal tissue within 1–2 days. nanocarriers should be much less than 400 nm. and to avoid the specific capture by the liver. (i) The ideal nanocarriers size should be somewhere between 10 and 100 nm. Thus extravasation of nanocarriers will vary with tumor types and anatomical sites. All nanocarriers use the EPR effect as a guiding principle. nanocarriers need to be larger than01 nm. some limitations exist. for almost all rapidly growing solid tumors the EPR effect is applicable. Indeed. (ii) The charge of the particles should be neutral or anionic for efficient evasion of the renal elimination. to reach passively the tumor. leaving diffusion as the major mode of drug transport. (i) The passive targeting depends on the degree of tumor vascularization and angiogenesis. according to a gradient of concentration. EPR effect can be observed in almost all human cancers with the exception of hypovascular tumors such as prostate cancer or pancreatic cancer. nanocarriers need to be smaller than 100 nm.The EPR effect is now becoming the gold standard in cancer-targeting drug designing. and without contribution of cellular energy. (ii) As previously mentioned. To this end. which destroys any foreign material through opsonization followed by phagocytosis Nevertheless. Selective accumulation of nanocarriers and drug then occurs by the EPR effect . Very high local concentrations of drug-loaded nanocarriers can be achieved at the tumor site. at least three properties of nanocarriers are particularly important. to avoid the filtration by the kidneys. On the other hand. convection through the tumor interstitium is poor due to interstitial hypertension. Indeed. Nevertheless.The EPR effect will be optimal if nanocarriers can evade immune surveillance and circulate for a long period. for efficient extravasation from the fenestrations in leaky vasculature. (iii) The nanocarriers must be hidden from the reticulo–endothelial system. The high interstitial fluid pressure of tumors associated with the poor lymphatic drainage 7 . Moreover.process of transport of molecules across the cell membrane.

By contrast. Active targeting In active targeting. (1) Nanocarriers reach tumors selectively through the leaky vasculature surrounding the tumors. (2) Figure 1. (2) 8 . 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. Targeting ligands are either monoclonal antibodies (mAbs) and antibody fragments or non antibody ligands (peptidic or not).explain the size relationship with the EPR effect: larger and long-circulating nanocarriers (100 nm) are more retained in the tumor. targeted receptors should be expressed homogeneously on all targeted cells. whereas smaller molecules easily diffuse.2. drug-loaded nanocarriers cannot diffuse back into the blood stream because of their large size. Moreover. Passive targeting of nanocarriers. resulting in progressive accumulation: the EPR effect 5. The ligand is chosen to bind to a receptor over expressed by tumor cells or tumor vasculature and not expressed by normal cells. targeting ligands are attached at the surface of the nanocarrier for binding to appropriate receptors expressed at the target site. (2) Schematic representation of the influence of the size for retention in the tumor tissue.

Prolonged circulation in the blood and ability to accumulate in various pathological areas (eg. eg. folate or transferrin. 6. Active targeting strategies. 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. Types of Nanoparticles Used as Drug Delivery systems Nanoparticles applied as drug delivery systems are submicronsized particles (3-200 nm). and even organometallic compound. or dendrimers). These functionalities are expected to provide nanocarriers: 1. lipids (liposomes). viruses (viral nanoparticles). Ligands grafted at the surface of nanocarriers bind to receptors (over)expressed by (1) cancer cells or (2) angiogenic endothelial cells. devices. or systems that can be made using a variety of materials including polymers (polymeric nanoparticles. solid tumors) via the EPR effect (protective polymeric coating with polyethylene glycol [PEG] is frequently used for this purpose) 2.Figure 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. are used for this purpose) 9 . micelles.

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. 6. Recently. amphiphilic core/shell (polymeric micelles).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. DNA. polystyrene-maleic anhydride copolymer. or hyper branched macromolecules (dendrimers). 4. Abraxane has also been evaluated in clinical trials involving many other cancers including non–small-cell lung cancer (phase II trial) and advanced nonhematologic malignancies (phase I and pharmacokinetics trials). has been applied in the clinic for the treatment of metastatic breast cancer. Besides metastatic breast cancer. as well as drugs. in which serum albumin is included as a carrier [nanometer-sized albumin bound paclitaxel (Abraxane).methacrylamide copolymer (HPMA). polyethylene glycol (PEG).The ability to respond to local stimuli characteristic of the pathological site by.1. HPMA and PEG are the most widely used nonbiodegradable synthetic polymers.3.or temperature sensitive components). chitosan. Polymers used as drug conjugates can be divided into two groups of natural and synthetic polymers. Polymeric nanoparticles (polymer-drug conjugates) Polymers such as albumin. the drug is either physically entrapped in or covalently bound to the polymer matrix. and poly-L-glutamic acid (PGA). Among synthetic polymers such as N-(2-hydroxypropyl) . for example. Polymer-based drug carriers Depending on the method of preparation.1. 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.1. and protein. The resulting compounds may have the structure of capsules (polymeric nanoparticles). and heparin occur naturally and have been a material of choice for the delivery of oligonucleotides. 10 . a nanoparticles formulation of paclitaxel. PGA was the first biodegradable polymer to be used for conjugate synthesis.

The hydrophobic core region serves as a reservoir for hydrophobic drugs. To overcome the poor solubility of certain drugs. On the other hand. since it he drug molecule to penetrate a cell membrane and reach important intracellular targets. thus minimizing undesired drug toxicity toward normal tissue. are another promising type of pharmaceutical carrier. poorly water. This is why micelles. eg.‖ It has been repeatedly shown that micelle-incorporated anticancer drugs.2. drug aggregation upon intravenous administration of poorly soluble drugs might lead to such complications as embolism and local toxicity. Kwon and Kataoka ) accumulate better in tumors than in non target tissues. Figure 3. Polymeric micelles (amphiphilic block copolymers). including polymeric micelles.soluble agents is associated with some serious problems. Micelles are colloidal dispersions with a particle size between 5 nm and 100 nm. The use of certain special amphiphilic molecules as micelle building blocks can also extend the blood half-life upon intravenous administration. such as adriamycin (see.1. the use of various micelle forming surfactants in formulations of insoluble drugs is suggested. (3) Because of their small size (5-100 nm). whereas the hydrophilic shell region stabilizes the hydrophobic core and renders the polymers 11 . particularly because large proportions of new drug candidates emerging from high throughput drug screening initiatives are water-insoluble. The therapeutic application of hydrophobic. but there are some unresolved issues. the hydrophobicity and low solubility in water appear to be intrinsic properties of many drugs. An important property of micelles is their ability to increase the solubility and bioavailability of poorly soluble pharmaceuticals.Polymeric micelle In addition.6. The development of drug nanocarriers for poorly soluble pharmaceuticals is an important task. 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. since low water solubility results in poor absorption and low bioavailability.

2001. In addition.. The drug can be loaded into a polymeric micelle in two ways: physical encapsulation or chemical covalent attachment.... making the particle an appropriate candidate for I..II or Phase-I/II stages of clinical trials (Hamaguchi et al. These ligands include proteins (including antibodies). 2008). For example. Torchilin et al. 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.V administration. Valle et al. 2010) (Table 1). 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. 2008). vitamins.water-soluble. 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. and future work involves targeting ligand addition within these constructs.. 2008). Wilson et al. 2007).. (4) 12 . Kabanov.. 2003b. 2008). 2008.Licciardi et al. 2006.. While encouraging.. 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. NK105 and NC6004 are also both micellar-based drugs currently in either Phase. In fact.. 2007. (4) Micelles containing a folate moiety have been shown to be significantly more cytotoxic to ovarian carcinoma cells than non-targeted micelles (Kim et al. 2004. as well as various carbohydrates (Nagasaki et al. all of these formulations passively deliver chemotherapeutics to cancer cells. Wang et al. 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) (Table 1).

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). the dendrimer most widely used as a scaffold. composed of multiple highly branched monomers that emerge radially from the central core.2. Properties associated with these dendrimers such as their monodisperse size. Liposome 13 . and available internal cavity make them attractive for drug delivery.1. water solubility. Dendrimers was conjugated with cisplatin. Dendrimers Dendrimer is a synthetic polymeric macromolecule of nanometer dimensions. modifiable surface functionality. multivalency. or therapeutic drugs.6. yielding a dendrimer-based multifunctional drug delivery system 6. Polyamidoamine dendrimer.3. Figure 4. The easily modifiable surface characteristic of dendrimers enables them to be simultaneously conjugated with several molecules such as imaging contrast agents. Figure 5. targeting ligands.

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.To obtain targeted liposomes.They are classified according to the number of lipid bilayers as either unilamellar or multilamellar. coated with PEG. anti-HER2 immunoliposomes have been shown to be far more cytotoxic in HER2-overexpressing breast cancer cells than non-targeted liposomes (Gao et al.e. drugs included in liposomes are protected from the destructive action of external media. (ie. that is. and peripheral neurotoxicity commonly associated with the use of both cisplatin and vincristine (Wang et al. the approach with immunoliposomes may nevertheless be limited because of their short life in the circulation. PEGylated) liposomes have attracted so much attention over the last decade. including antibodies. to the liposome surface without affecting the liposome integrity and antibody properties. (4) However. increasing the total quantity of immunoliposomes passing through the target and increasing their interactions with target antigens. Unilamellar systems have an aqueous core for encapsulation of water soluble drugs. Dramatically better accumulation can be achieved if the circulation time of liposomes is extended.. 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. For example. 2000. liposomes selectively accumulating inside an affected organ or tissue. This is why long circulated (usually. 2001. In any event. 2003). many protocols have been developed to bind corresponding targeting moieties.. whereas multilamellar systems entrap lipid soluble drugs. 2007a. doxorubicin) (Rivera. The cancer cell surface receptor CD44. (5) They are biologically inert and completely biocompatible. The use of targeted liposomes. and they cause practically no toxic or antigenic reactions.. 2009). Bianchi et al. 2006) 14 . Rezler et al. increases the efficacy of the liposomal drug and decreases the loss of liposomes and their contents in the reticuloendothelial system (RES).. 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.

and single-chain antibodies have been conjugated to viruses for specific tumor targeting in vivo. such as canine parvovirus. Besides this artificial targeting. Therefore. 6. Targeted Pharmaceutical Nanocarriers for Cancer Therapy and Imaging. a dual-function protein cage with specific targeting and doxorubicin encapsulation has been developed. Viruses Viral nanoparticles A variety of viruses including cowpea mosaic virus. several ligands or antibodies including transferrin. ovarian cancer. Caelyx) Vincristine (Onco TCS) Lurtotecan (NX211) Kaposi ’ s sarcoma Combinational therapy of recurrent breast cancer Refractory Kaposi ’ s sarcoma. and bacteriophages have been developed for biomedical and nanotechnology applications that include tissue targeting and drug delivery. has natural affinity for receptors such as transferrin receptors that are up-regulated on a variety of tumor cells. 9 (2): E128-E147. folic acid. a subset of viruses. (6) 15 . 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. A number of targeting molecules and peptides can be displayed in a biologically functional form on their capsid surface using chemical or genetic means.3. By targeting heat shock protein. cowpea chlorotic mottle virus. American association of pharmaceutical scientists. recurrent breast cancer Non-Hodgkin ’ s lymphoma Ovarian cancer Indications Source: Vladimir P.Table 1. canine parvovirus. Torchilin. (2007).

Antifungal agents (amphotericin B) or anticancer drugs (methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent (FITC). and therapeutic agents. generating some health concerns and toxicity problems. Carbon nanotube carbon nanotubes can render them water. Carbon nanotubes are completely insoluble in all solvents. Carbon nanotubes Carbon nanotubes are carbon cylinders composed of benzene rings that have been applied in biology as sensors for detecting DNA and protein. The multiple covalent functionalizations on the sidewall or tips of carbon nanotubes allow them to carry several molecules at once. and carriers to deliver vaccine or protein . However.soluble and functionalized so that they can be linked to a wide variety of active molecules such as peptides. diagnostic devices for the discrimination of different proteins from serum samples. 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. nucleic acids. (6) 16 . the introduction of chemical modification to Figure 6. In an in vitro study. and this strategy provides a fundamental advantage in the treatment of cancer.6. proteins.4.

liquids. Nanocapsules These particles are vesicular systems with a central cavity or core to which a drug is confined. Nanospheres These nanoparticles are spherical structures composed of a matrix system in which drug is distributed by entrapment.6.5. The core is surrounded by an outer shell polymeric membrane to which surface bound targeting ligands or antibodies may be attached. Nanosphere 6. Nanocapsule 17 .5. and the core environment may be aqueous or oily. The core material may be solids. attachment. 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. (5) Figure 7. or encapsulation. (5) Figure 8.1. or gas. Others 6.2.5.

Drugs are encapsulated within these polymeric matrices. the system is triggered to release the anticancer drug in response to pH stimuli. Figure. thus antitumor drugs that are encapsulated or conjugated into carrier materials could be released rapidly in the acidic microenvironment of tumor tissues (Fig.3. or is taken up by cancer cells after binding to target antigens on the surface of the cancer cells. 18 . 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. 9). shape or hydrophobicity.PHresponsive nanocarriers accumulate in the tumor tissue via the enhanced permeability and retention (EPR) effect through the leaky blood vessels. the antitumor drug should be released rapidly from carrier (1) materials in the acidic microenvironment of endosomes/lysosomes.5.9 Schematic representation of pH-responsive nanocarriers targeting.6. It is wellknown that tumor tissues have lower pH than normal tissues. In order to improve the therapeutic effect of anticancer drugs that target the nucleus or other organelles or cytoskeletal structures after cellular uptake. After pH-responsive nanocarriers accumulate in the tissue. In this latter case the drugs are released inside the cancer cells by pH in stimuli.

5. Nanoparticles in clinical use Despite extensive research and development. only a few drug delivery nanoparticles currently are FDA approved and available for cancer treatment. an albumin bound paclitaxel nanoparticle Abraxane was recently approved by the FDA for the treatment of breast cancer. Mixed nanoparticles. Two commercial liposomal formulations are available in the United States. siRNA nanoparticles were first designed with Poly (Propyleneimine) (PPI) dendrimers. RNAi and ASO therapies can shut down the expression of target genes to treat the disease.) and liposomal daunorubicin (DaunoXome). The remaining parts of this discussion will focus on those nanoparticles approved and marketed for clinical oncology use. Based on oligonucleotides.6. Nucleic acid –based nanoparticles (DNA.S. (5) 19 .S. Adding to this formulary. These are pegylated liposomal doxorubicin (Doxil in the U. Liposomal anticancer drugs were the first to be approved for therapy in cancer. (7) 7. A third liposomal formulation approved in Europe is nonpegylated liposomal doxorubicin (Myocet). 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. were confirmed to be effective for both in vitro and in vivo gene delivery to colon and liver cancer cells.4. and Caelyx outside the U. prepared with generations 4 and 5 poly (amidoamine) (PAMAM) dendrimers and plasmid DNA. RNA and ASO) Gene therapy refers to the direct transfer and expression of DNA into diseased cells for the therapeutic applications. Recently.

but not eliminated [27. (5) 20 . It also adds steric stabilization to prolong the plasma t1/2. the anthracycline pharmacokinetics are altered and cardiac risk is decreased. The recommended systemic dosage for Doxil is 40 to 50 mg/m2 infused over 1 hour every 4 weeks. 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. After extravasation through tumor endothelium. The FDA approved three major indications for pegylated liposomal doxorubicin—AIDS related Kaposi’s sarcoma.7.fold higher in tumor tissue compared with conventional free drug administration. High peak plasma concentrations of anthracycline are associated with risk for congestive cardiomyopathy as is the lifetime cumulative dose of the drugs. platinum pretreated ovarian cancer. anthracycline toxicity to normal tissue. (5) 7. Doxil liposomes disintegrate and deliver doxorubicin. The main toxicities are palmar plantar skin reactions (PPE) and stomatitis/mucositis. Doxil has less cardiotoxicity.1. and first line monotherapy of metastatic breast cancer. Drug concentration has been measured at 10. Liposomal anthracyclines The available liposomal formulations represent encapsulated anthracyclines— doxorubicin in Doxil and Myocet and daunorubicin in DaunoXome. are reduced by liposomal encapsulation.1. including alopecia and myelosuppression. and vomiting. By liposomal encapsulation. The polyethylene glycol coating (pegylation) prevents opsonization and avoids RES clearance. alopecia. While anthracyclines are highly active cytotoxic drugs. Additionally. myelosuppression. they have significant toxicity associated with their use both acute and cumulative. nausea.1.28]. Compared with a conventional doxorubicin infusion.

the drug is encapsulated in a small unilamellar liposome (45 nm size). (5) 7. Due side effects.1. due to solubility problems. a modified adriamycin/bleomycin/vincristine (ABV) regimen. The FDA approved indication for pegylated daunorubicin is for the treatment of Kaposi’s sarcoma. Both of these drugs are hydrophobic and. Pegylated daunorubicin (DaunoXome) Due to the relative stability of daunorubicin in aqueous solution. Paclitaxel and docetaxel are the commercially available taxanes for clinical treatment. 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. These solvents can cause severe hypersensitivity reactions and toxicities.2. Toxicities differed significantly with more grade 4 neutropenia for pegylated daunorubicin and greater alopecia and neuropathy for ABV. Patients must be premedicated with steroids and 21 . Overall response rates and median survival were not different between the two groups. 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.7.2. are formulated with a solvent paclitaxel with Cremophor-EL and Tween-80 for docetaxel. A Phase III trial randomized chemo naïve Kaposi’s sarcoma patients to pegylated daunorubicin vs.

leading to the formation of a caveolae that is released into the extravascular space. Albumin paclitaxel molecules bind to an albumin receptor (gp60) on endothelial cells that transports the hydrophobic paclitaxel into the extravascular space. A pivotal Phase III trial of 460 women compared nab-paclitaxel with conventional paclitaxel on a 3-week schedule. since nab-paclitaxel is solvent free. Therefore. Overall survival was not significantly different for all patients. To decrease the toxic effects associated with these drugs. SPARC protein can bind albumin and can increase the concentration of the albumin bound paclitaxel particle in the tumor due to such binding. 19% and times to progression significantly longer 23 weeks for nab paclitaxel vs. Toxicity profiles differed with nab-paclitaxel having less neutropenia compared to taxol but more grade 2 and 3 sensory neuropathy. A second proposed transport pathway for the nanoparticles is via secreted protein acidic rich in cysteine (SPARC). SPARC protein represents another transport mechanism for nabpaclitaxel into tumor cells Based on these properties. the infusion time is 30 minutes compared with the 3-hour infusion for conventional taxol. SPARC expression has been reported in many solid tumors including bladder and prostate cancers and is associated with a poor prognosis. the drug must also be slowly infused over several hours. The FDA approved nab-paclitaxel for metastatic breast cancer therapy after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. The technology for particle formation involves a proprietary process that binds unmodified albumin to the paclitaxel molecule yielding a nanoparticle of 130 nm size. and.antihistamines prior to drug infusion. 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. Overall response rates were significantly higher for nab-paclitaxel 33% vs. a nanoparticle formulation has been developed for paclitaxel. Other names for this protein are BM40 and osteonectin. these particles rapidly dissociate to yield an albumin bound drug complex. The albumin receptors (gp60) cluster on endothelial surfaces and associate with caveolin-1. 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. All patients were taxane naïve. After infusion. All patients in this trial had 22 . For paclitaxel. caveolae are a major transport mechanism for nab-paclitaxel. Hence. 17 weeks. and no premedication is required.

Cell line and mouse xenograft studies of this molecule suggest great potential for therapeutic application in humans. enhanced cellular toxicity is noted compared with the same NP lacking aptamers. the NP escapes rapid RES clearance. Docetaxel encapsulated nanoparticle aptamer bioconjugate This docetaxel encapsulated nanoparticle with the copolymer poly (D. Finally. (5) 7.previously been treated with paclitaxel. The RNA aptamer is an oligonucleotide capable of binding to the target antigen PSMA with high affinity and specificity. Nab-paclitaxel represents an alternative treatment option for such cancer patients treated with conventional taxanes who develop resistance or toxicity intolerance.3.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 polymers allow sustained intracellular drug release. the choice of docetaxel utilizes a cytotoxic drug already proven in clinical trials to prolong survival of (5) hormone resistant prostate cancer in humans. This concept has particular implications for urologic cancers. notably prostate. The aptamer binds to PSMA on the surface of LNCaP prostate epithelial cells and then is internalized into the cell. and were refractory. The observed response rates for the weekly nab-paclitaxel suggested that the drug was non-cross resistant for taxane refractory patients. 23 . or both drugs. The technology supporting the molecule design included utilizing biocompatible and biodegradable polymers with established safety for human use. With the polymer coat. a malignancy in which the only proven agent to prolong survival is a taxane. docetaxel. As a result.

novel ligands. Conclusion Nanotechnology is new area in research that provides several advantages for drug delivery systems especially for anticancer drugs. drug solubility and particle stabilization. In the future this field will expand and involve new approach and strategies in tumor targeting. 24 .8.