types of nano particles used as drug delivery systems

7/31/2019 Types of Nano Particles Used as Drug Delivery Systems

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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 wayspassive 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).....76.1.3. 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 acidbased nanoparticles (DNA, RNA and ASO).15

7. Nanoparticles in clinical use...15

7.1. Liposomal anthracyclines..16

7.1.1. Pegylated liposomal doxorubicin (Doxil)167.1.2. 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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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


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1. Table 1: Some Examples of Liposomal Drugs Approved for Clinical Application or

Undergoing Clinical Evaluation for Cancer Therapy11


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EPR enhanced permeability and retentionHPMA N-(2-hydroxy propyl)-methacrylamide

copolymer

PEG poly ethylene glycol

PGA poly-L- glutamic acid

HA hyaluronic acid

ASO anti sense oligonucleotides

Si RNA small interfering RNA

PEI poly ethylen imine

PAMAM poly amido amine

PPI poly propylene imine

RES reticuloendothelial system

PSMA prostate specific membrane antigen

LNCAP androgen sensitive human prostate

adencarcinoma cells

PLGA-b-PEG poly (D, L- lacti - co- glycolic acid)

block - poly ethylene glycol


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1. Abstract

Nanocarriers is new approach in drug delivery system that enhance properties of the

drugs such as improve pharmacokinetics and pharmacodynamics , improve solubilityand 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.(1)


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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. (2)

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 fluids.

Convection must be the predominating transport mode for most large molecules

across large pores when the net filtration rate is zero. In the contrary, low molecularweight compounds, such as oxygen, are mainly transportedby diffusion, defined 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 efficient extravasation from the fenestrations in leaky vasculature, nanocarriers

should be much less than 400 nm. On the other hand, to avoid the filtration by the

kidneys, nanocarriers need to be larger than 01 nm; and to avoid the specific capture

by the liver, nanocarriers need to be smaller than 100 nm.

(ii) The charge of the particles should be neutral or anionic for efficient 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 fluid pressure of solid tumors avoids

successful uptake and homogenous distribution of drugs in the tumor . The highinterstitial fluid 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.(2)

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)


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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 surface-

attached specific ligand (monoclonal antibodies as well as their Fab fragments and

some other moieties, eg, folate or transferrin, are used for this purpose)


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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.(3)

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 effecta 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). (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., 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).(4)


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6.1.3. Dendrimers

Dendrimer is a 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.(5)

They are biologically inert and completely biocompatible, and they cause practicallyno 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.(4)

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) Indications

Daunorubicin (DaunoXome) Kaposi s sarcoma

Doxurubicin (Mycet) Combinational therapy of recurrent breast cancer

Doxorubicin in polyethylene glycol liposomes (Doxil, Caelyx) Refractory Kaposi s sarcoma; ovarian cancer;

recurrent breast cancer

Vincristine (Onco TCS) Non-Hodgkin s lymphoma

Lurtotecan (NX211) Ovarian cancer

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 numberof 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.(6)


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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.(6)


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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.(5)

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. (5)

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 well-

known 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 materials in the acidic microenvironment of

endosomes/lysosomes. (1)

Figure.9 Schematic representation of pH-responsive nanocarriers targeting.PH-

responsive 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 acidbased 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.(7)

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.(5)


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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.(5)

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.(5)


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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 increased AUC

compared to 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. (5)

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 nab-

paclitaxel 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 andreported 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.(5)

7.3. Docetaxel encapsulated nanoparticle aptamer bioconjugate

This docetaxel encapsulated

nanoparticle with the copolymer poly

(D,L-lacti-co-glycolic acid) block-

poly (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 thepolymer 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

hormone resistant prostate cancer in humans.(5)


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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.

types of nano particles used as drug delivery systems

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