Polymeric Nano Medicine for Cancer Therapy-Review

 

Durgadevi, Indumathi, Gayathri P.K.*

Department of Biotechnology, Vel Tech High Tech Dr. Rangarajan Dr. Sakunthala Engineering College, Chennai.

 

ABSTRACT:

Most anti-cancer drugs are based on a differential killing of cancer cells. Development of cancer therapy has largely been driven by the assumption that if we screen enough drugs we will find drugs with a mechanism of action which allows a greater discrimination between normal cells and cancer cells. From a biochemical (or pharmacological) point of view there is very little difference between normal and cancer cells, i.e. pharmacological specificity of anticancer agents is very low for most cancers. So the drug delivery systems should try to exploit the differences between cancer and normal cells because of differences in accessibility - physiological/anatomical factors. In the past few decades, considerable attention has been focused on the development of novel drug delivery system (NDDS) for anticancer drugs. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. This review focuses on the development of polymer nanomedicines, its pre-clinical and clinical investigations and the future perspectives.

 

 

 

INTRODUCTION:

The standard of care for cancer patients comprises more than one therapeutic agent. Treatment is complex since several drugs, administered by different routes, need to be coordinated, taking into consideration their side effects and mechanisms of resistance. Drug delivery systems (DDS), such as polymers and liposomes, are designed to improve the pharmacokinetics and efficacy of bioactive agents (drugs, proteins or oligonucleotides), while reducing systemic toxicity. Using DDS for co-delivery of several agents holds great potential since it targets simultaneously synergistic therapeutic agents increasing their selective accumulation at the tumor site and enhancing their activity allowing  administration  of  lower doses of each agent, thus reducing their side effects. Taken together, implementation of smart DDS will hopefully result in increased patient's compliance  and  better  outcome. This review will focus on the latest developments of combination therapy for cancer using DDS.

 

Specificity of Nanomedicine

Nano materials are similar in scale to biological molecules and systems yet can be engineered to have various functions,nanotechnology is potentially useful for medical applications.The field of nanomedicine is aims to use the properties and physical charecteristics of nonmaterial for the diagnosis and treatment of diseases at the molecular level.

 

Nanomaterials are now being designed to aid the transport of diagnostic or therapeutic agents through biologic barriers; to gain access to molecules; to mediate molecular interactions; and to detect molecular changes and to detect molecular changes in sensitive, high-throughput manner. In contrast to atoms and macroscopic medicines, nanomedicines have a high ratio of surface area to volume.                                          

A polymer used in controlled drug delivery formulations, must be chemically inert, non-toxic and free of leachable impurities. It must also have an appropriate physical structure, with minimal undesired aging, and be readily processable. Some of the polymeric materials are listed below

 

·        Cellulosics.

·        Poly(2-hydroxy ethyl methacrylate).

·        Poly(N-vinyl pyrrolidone).

·        Poly(methyl methacrylate).

·        Poly(vinyl alcohol).

·        Poly(acrylic acid).

·        Polyacrylamide.

·        Poly(ethylene-co-vinyl acetate).

·        Poly(ethylene glycol).

·        Poly(methacrylic acid).

 

In recent years additional polymers are designed primarily for medical applications and have entered the arena of controlled release of bioactive agents. Many of these materials are designed to degrade within the body, most popular ones are

·        Polylactides (PLA).

·        Polyglycolides (PGA).

·        Poly(lactide-co-glycolides) (PLGA).

·        Polyanhydrides.

·        Polyorthoesters.

·        Polycyanoacrylates

·        Polycaprolactone

 

Originally, polylactides and polyglycolides were used as absorbable suture material. The main advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. However, biodegradable materials do produce degradation by-products that must be tolerated with little or no adverse reactions within the biological environment. The size of anticancer agent-incorporating micelles can be controlled within the diameter range of 20-100 nm to ensure that they do not penetrate normal vessel walls. With this development, it is expected that the incidence of drug-induced side-effects may be decreased owing to the reduced drug distribution in normal tissue. Micelle systems can also evade non-specific capture by the reticuloendothelial system because the outer shell of a micelle is covered with polyethylene glycol. Consequently, a polymer micelle carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Moreover, a water-insoluble drug can be incorporated into polymer micelles. Presently, several anticancer agent-incorporating micelle carrier systems are under preclinical and clinical evaluation.

 

Micelles as nano polymer:

Similar to the spheroidal structure of liposomes, micelles are aggregates of surfactant or polymer dispersed in an aqueous solution but do not have an internal aqueous phase like that of liposomes .Polymeric micelles have the same advantages as other polymeric formulations and liposomal formulations :namely the protection of the therapeutic agent from degradation and increased circulation of the drug. Generally polymeric micelles are made with two different polymers: a hydrophilic shell with that is responsible for colloidal stability and protects the active ingredient and a hydrophobic core polymer that either physically or chemically protects the active ingredient. polymeric micelle technology has advanced furthest in the oncology. Currently, Genexol-PM has ongoing phase II trials for pancreatic cancer ,  ovarian cancer, and non-small-cell lung cancer , and phase III and phase IV trials in patients with recurrent breast cancer , studying the toxicity , progression-free survival , and tumor control rate.

 

Lipid-Based Nanoparticles:

Liposomal drug carriers may be the most prolific nanomedicine technology currently on the market. Liposomes are composed of one or more concentric lipid bilayers encapsulating an inner aqueous core. Their ubiquitous use in pharmaceutical formulations is because the outer lipid layer of liposomes protects the encapsulated drug from the external environment and because the outer surface can be functionalized to improve targeting. Some examples of liposomal drug formulations approved by the FDA are listed in TABLE 1.

 

 

Indicated for recurrent ovarian cancer, relapsed/refractory multiple myeloma, and AIDS-related Kaposi’s Sarcoma, Doxil highlights some of the benefits of liposomal technology to improve drug delivery. Doxil’s liposomal shell surrounding the doxorubicin molecules is coated with polyethylene glycol (PEG). The liposomal carrier increases the blood circulation time of the drug, and the polymer PEG lends the liposome “stealth” qualities, largely avoiding the immune system. The prolonged blood circulation time of Doxil results in the passive accumulation of the drug at the tumor site by the EPR effect.

 

 

Likewise, the array of nanotechnology products being applied to medicine is equally as varied: magnetic nanoparticles, quantum dots, liposomes, nanocrystals, nanosuspensions, gold nanoparticles, microspheres, carbon nanotubes, and other polymeric nanoparticle designs. While most of these technologies are still in preclinical development, there is a growing list of nanomedicine-enabled products already on the market and in clinical trials. This review focuses on those products and product candidates for therapeutic applications in medicine that are beyond preclinical development, discussing the purpose and advantages of integrating nanotechnology with pharmaceutics. TABLE 1 lists some of the FDA-approved drugs that have been developed or improved by nanomedicine techniques.

 

 

Table Select FDA Approved Agents utilizing Nanomedicine             

Product		Composition	Indication	Approved
Lipid-Based Nanoparticles
Abelcet	Lipid complex formulation of amphotericin B		Invasive fungal infections	1995
AmBisome	Liposomal preparation of amphotericin B		Fungal and protozoal infections	1997
DaunoXome	Liposomal preparation of daunorubicin		HIV-related Kaposi’s sarcoma	1996
Depocyt	Liposomal formulation of cytarabine		Lymphomatous meningitis	1999
DepoDur	Liposomal formulation of morphine sulphate		Relief of postsurgical pain	2004
Doxil/Caelyx	PEGylated liposomal formulation of doxorubicin		Various Cancers	1995
Inflexal V	Liposomal influenza vaccine		Influenza	1997
Visudyne	Liposomal formulation of verteporfin		Wet age-related macular degeneration	2000
Polymer-Based Nanoparticles
Adagen	PEGylated adenosine deaminase enzyme		Severe combined immunodeficiency disease	1990
Cimzia	PEGlyated Fab’fragment of a Humanized anti-TNF-alpha  ntibody		Crohn’s disease, rheumatoid arthritis	2008
Copaxone	Polymer composed of L-glutamic acid, L-alanine , L-lysine , and L-tyrosine		Multiple sclerosis	1996
Eligard	Leuprolide acetate and PLGH polymer formulation		Advanced prostate cancer	2002
Macugen	PEG-anti-VEGF aptamer		Neovascular age-related macular degeneration	2004
Mircera	Chemically synthesized ESA, Methoxy PEG-epoetin beta		Symptomatic anemia associated with chronic kidney disease	2007
Neulasta	Conjugate of PEG and filgrastim		Chemotherapy-induced neutropenia	2002
Oncaspar	PEGylated formulation of L-asparaginase		Acute lymphoblastic leukemia	1994
Pegasys	PEGylated interferon alfa-2a		Hepatitis C	2002
PegIntron	PEGylated interferon alfa-2b		Hepatitis C	2001
Renagel	Polyamine ( polymer loaded with amine groups)		Chronic kidney disease	200
Somavert	PEGylated human growth hormone receptor antagonist		Acromegaly	2003
Protein-Based Nanoparticles
Abraxane		Albumine-bound paclitaxel	Breast cancer	2005

The application of nanotechnology to the drug development process allows scientists to design and develop nanoscale pharmaceuticals that meet the size requirements necessary to achieve passive targeting. By virtue of their size and unique surface properties, nanoparticles are also capable of active targeting to diseased cells in order to deliver drugs at a higher concentration while reducing drug-related side effects by preventing or reducing the interaction with normal cells. Administration of drugs via nanoparticles allows manipulation of the absorption, distribution, metabolism, and elimination (ADME) of drugs and increases the overall therapeutic effect.

 

Additional Nanomedicine Platforms:

Another field of research under the umbrella of nanomedicine is the utilization of nanoemulsions in drug delivery. Nanoemulsions are stabilized nano-sized oil droplets emulsified in water. The oil droplets can range in size from 10 to 500 nm in diameter and act as carriers for water-insoluble drug compounds.

 

Future of Nanomedicine:

The impact of nanomedicine in drug delivery is unmistakable. The product candidates discussed in this review are not the only nanomedicine products being investigated in clinical trials today, but they do accurately represent the spectrum of nanoparticles used in drug delivery. Moreover, this review does not take into account the thousands of other products that are in preclinical development. With adequate evaluation of the possible toxicities of nanoparticles and with continued nanotechnology innovations related to complex diseases such as cancers, the list of nanomedicine-enabled products will continue to experience positive growth in the future.

 

REFERENCES:

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7.       FDA approved drug products. Drugs@FDA. www.accessdata. fda.gov/scripts/cder/drugsatfda/. Accessed February 8, 2011.

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Received on 29.08.2013                             Accepted on 01.09.2013        

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