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ISSN: 2249-7196 IJMRR/March 2015/ Volume 5/Issue 3/Article No-9/211-214 Vikas Kumar Chhajed / International Journal of Management Research & Review *Corresponding Author www.ijmrr.com 211 NEWER METHODS, ADVANCEMENTS AND APPLICATIONS OF RADIATION POLYMERIZATION IN NEW DRUG DEVELOPMENT AND DELIVERY Dr. Pradeep K Jha* 1 , Dr. Rakhi Jha 1 , Dr. Soma Das 2 , Prof Sujoy K Guha 1 , Dr.Rajul Dutt 3 1 School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, India. 2 Vidyasagar University, Midnapore, West Bengal, India. 3 J. P School of Business, Meerut, India. ABSTRACT Radiation polymerization or synthesis of polymer based drugs by the mean of radiation procedure is one of the main aspects of chemistry today. Radiation synthesis has proven itself to be advantageous in respect to its simplicity, efficiency, cleanliness & being an environment–friendly process. As the process usually combines synthesis & sterilization in a single technological step, it results into reduction of cost & production time. Efficient application & further broadening of the procedure require exploring the underlying science of polymer chemistry. One of the best practices in polymer chemistry is formation of two or multicompartment systems comprising of three dimensional structure & water filling the space between macromolecules, which are called hydrogels. Major methods for radiation synthesis involve irradiation of solid polymers, irradiation of monomers & irradiation of aqueous solution of polymers. Radiation grafting is a boon for modulating & modifying polymer structures for different biomedical applications. Keywords: Gamma Radiation, Polymer designing, Molecular weight. 1. INTRODUCTION Irradiation of polymers by gamma rays, X rays, electron beams, ion beams lead to the formation of reactive intermediates in the form of excited states, free radicals, ions. These intermediates are used to contrive several structurally modified polymers. Major mechanism of action behind the formation of these polymers is crosslinking, grafting, oxidization, scissioning. As because no catalyst or additives are required in initiation of radiation polymerization, it has got many advantages over common methods. So far till today there is an extensive surge to incorporate the belief that radiation technique can not only be used in sterilization procedure but also can be used in new drug development. This kind of new dug development may open up new domains in clinical, pharmacological & biomedical aspects. On the other side administration of drug from polymer based system provides good pharmacokinetic & pharmacodynamic property of a particular drug (1). The influence of irradiation sterilization has presently been used for polyester, poly (ortho ester), different synthetic hydrogels, silicone derivatives, cellulose-derivatives, hyaluronic acid, different

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ISSN: 2249-7196

IJMRR/March 2015/ Volume 5/Issue 3/Article No-9/211-214

Vikas Kumar Chhajed / International Journal of Management Research & Review

*Corresponding Author www.ijmrr.com 211

NEWER METHODS, ADVANCEMENTS AND APPLICATIONS OF RADIATION

POLYMERIZATION IN NEW DRUG DEVELOPMENT AND DELIVERY

Dr. Pradeep K Jha*1, Dr. Rakhi Jha

1, Dr. Soma Das

2, Prof Sujoy K Guha

1, Dr.Rajul Dutt

3

1School of Medical Science and Technology, Indian Institute of Technology, Kharagpur,

India.

2Vidyasagar University, Midnapore, West Bengal, India.

3J. P School of Business, Meerut, India.

ABSTRACT

Radiation polymerization or synthesis of polymer based drugs by the mean of radiation

procedure is one of the main aspects of chemistry today. Radiation synthesis has proven itself

to be advantageous in respect to its simplicity, efficiency, cleanliness & being an

environment–friendly process. As the process usually combines synthesis & sterilization in a

single technological step, it results into reduction of cost & production time. Efficient

application & further broadening of the procedure require exploring the underlying science of

polymer chemistry. One of the best practices in polymer chemistry is formation of two or

multicompartment systems comprising of three dimensional structure & water filling the

space between macromolecules, which are called hydrogels. Major methods for radiation

synthesis involve irradiation of solid polymers, irradiation of monomers & irradiation of

aqueous solution of polymers. Radiation grafting is a boon for modulating & modifying

polymer structures for different biomedical applications.

Keywords: Gamma Radiation, Polymer designing, Molecular weight.

1. INTRODUCTION

Irradiation of polymers by gamma rays, X rays, electron beams, ion beams lead to the

formation of reactive intermediates in the form of excited states, free radicals, ions. These

intermediates are used to contrive several structurally modified polymers. Major mechanism

of action behind the formation of these polymers is crosslinking, grafting, oxidization,

scissioning. As because no catalyst or additives are required in initiation of radiation

polymerization, it has got many advantages over common methods. So far till today there is

an extensive surge to incorporate the belief that radiation technique can not only be used in

sterilization procedure but also can be used in new drug development. This kind of new dug

development may open up new domains in clinical, pharmacological & biomedical aspects.

On the other side administration of drug from polymer based system provides good

pharmacokinetic & pharmacodynamic property of a particular drug (1). The influence of

irradiation sterilization has presently been used for polyester, poly (ortho ester), different

synthetic hydrogels, silicone derivatives, cellulose-derivatives, hyaluronic acid, different

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Copyright © 2012 Published by IJMRR. All rights reserved 212

glucosides, collagen, and gelatin. Also, some limitations concerning the use of high-energy

radiations for sterilization are there but still apart from sterilization, irradiation can be used

for drug development. This novel use of irradiation procedure may lead towards path

breaking developments in pharmaceutical & biomedical field with which this review has

further dealt (2).

2. POLYMERS & POLYMERIZATION

Polymer is a term used since 1866 by Berthelot who, in an article published in the Bulletin of

the Chemical Society of France, noted that “styrolene (styrene), heated at 200° during a few

hours, transforms itself into a resinous polymer”. It was the first recognized synthetic

polymer. But it was Hermann Staudinger, in the year 1920, which was the first to propose

the concept of polymers in the sense we use today. It lead to the Nobel Prize in 1953 for his

work which is at the base of all science of macromolecules.

Man had always used natural polymers in the form of textile fibres and material shapes. The

scarcity of some of them had mobilized researchers, at the end of 19th

century, to transform

natural polymers into artificial polymers. Thus, they created nitrocellulose (celluloid,

artificial silk) for the replacement of the ivory, silk…, or many materials presenting of the

new properties likely to generate new applications (ebonite by extreme vulcanization of the

natural rubber).

An important stage had been reached with the industrial production of the first synthetic

polymers (Bakelite, synthetic rubbers). But it is a result of the theory suggested by Staudinger

that their variety increased in a considerable way. He was the seminal researcher and the

majority of synthetic polymers used today result from its work (3).

The process of polymerization can be broadly classified into 2 types –

2.1 Addition polymerization

In this process, the double bonds between atoms in the monomers are induced to open up so

that they join with other monomer molecules. The connections occur on both ends of the

expanding macromolecule, developing long chains of repeating monomers It is initiated using

a chemical catalyst (called an initiator) to open the double bond in some of the monomers.

Fig 1: Mechanism of addition polymerization

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2.2 Step polymerization

In this form of polymerization, two reacting monomers are brought together to form a new

molecule of the desired compound. As reaction continues, more reactant molecules combine

with the molecules first synthesized to form polymers of length n= 2, then polymers of length

n=3, and so on. In addition, polymers of length n1 and n2 also combine to form molecules of

length n = n1+n2, so that two types of reactions are proceeding simultaneously.

Fig 2: Mechanism of step polymerization

3. APPLICATION OF POLYMERS & POLYMERIZATION IN BIOMEDICAL

FIELD

Polymers are becoming increasingly important in the field of drug delivery. The

pharmaceutical applications of polymers range from their use as binders in tablets to viscosity

and flow controlling agents in liquids, suspensions and emulsions. Polymers can be used as

film coatings to disguise the unpleasant taste of a drug, to enhance drug stability and to

modify drug release characteristics (4).

Research in natural polymeric materials has witnessed growing interest and attention. This is

attributable to a number of factors which include their relative abundance, low cost, and

biodegrable and eco-friendly profiles (5). Drugs are hardly administered as such but are

almost always formulated into a suitable dosage form with the aid of excipients, which serve

various functions such as binding, lubricating, gelling, suspending, flavoring, sweetening and

bulking agent among others (6). Some of the naturally occurring polymers having vast

application in pharmaceutical field are cellulose, hemicelluloses, pectin, alginates, guar gum,

xanthum gum etc.

Over the past decades, research at the level of molecular biology has unveiled the molecular

basis for many diseases. New important technologies and concepts, such as recombinant

DNA and gene therapy, have provided tools for the creation of pharmaceuticals and methods

designed to specifically address such diseases. However, progress towards the application of

these medicines outside of the laboratory has been considerably slow, principally due to the

lack of effective drug delivery systems, that is, mechanisms that allow the release of the drug

into the appropriate body compartment, for the appropriate amount of time, without seriously

disrupting the rest of the organism functionality.

There have been a growing number of different approaches to counter this issue, each with its

own particular applications, given the pathophysiology of the disease. Polymers, and

associated nanomedicine technologies, constitute a relatively new and promising approach

that has already been proven effective in a wide range of applications.

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Recently a new term has been coined, that is, ‘Polymer therapeutics’ which substantiates the

extensive use of polymers in therapeutics & biomedical field. This covers mainly two aspects

like polymer-protein conjugates & polymer-drug conjugates.

Fig 3: Polymer conjugates with length (7)

3.1 Polymer – protein conjugate:

Polymer-protein conjugation can be seen as an approach to increase the efficiency of protein,

peptide and antibody based drugs, given the vast range of these medicines that are being

created as a result from genomics and proteomics research, associated with new technologies

such as recombinant DNA and monoclonal antibodies. Their limitations often include a short

plasma half-life, poor stability, and, especially in the case of proteins, immunogenicity (8).

Research done in the 1970’s foresaw the potential of binding the polymer PEG (polyethylene

glycol) to proteins and since then a great progress was achieved. Nowadays, the advantages

of this technique have become evident. It is used in a wide variety of products, including

enzymes, cytokines and monoclonal antibody fragments. PEGylation has been proven to

provide among other things, increased protein solubility and stability, reduce receptor-

mediated protein uptake by cells of the reticuloendothelial system (7), reduce protein

immunogenicity, prevent the rapid renal clearance of small proteins, and prolonging plasma

half-life, thus requiring less frequent dosing, which is of great patient benefit (7).

The first polymer-protein conjugate to enter the market was PEG-adenosine deaminase in

1990. Since then, others have followed (Table A). PEG-L-asparaginase, for instance, is used

as a treatment for acute lymphoblastic leukaemia, with the advantage of reduced

hypersensitivity reactions when compared to the native enzyme. Other PEGylated protein

compounds includes PEG-G-CSF (G-CFS stands for a recombinant methionyl human

granulocyte colony-stimulating factor, which is used to prevent cancer chemotherapy induced

neutropaenia, with the advantage of requiring less frequent dosing when compared to free G-

CSF. In addition to proteins, PEG has also been used to produce a number of polymer-

cytokines conjugates. Two PEG-interferon-α conjugates, which have shown better activity in

vivo compared to IFN-α, have been approved as treatments for hepatitis C.

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Table 1: Some examples of widely used polymer-protein conjugates

Compound Status Indications

PEG-adenosine-

deaminase

Market Hepatocellular carcinoma

PEG-l-asparaginase Market Acute lymphoblastic leukaemia

PEG-GCSF Market Prevention of neutropaenia associated with cancer

chemotherapy

PEG-IFNα2a Market /

Phase I/II

Hepatitis B and C / Melanoma, chronic myeloid

leukaemia and renal-cell carcinoma

PEG-IFNα2b Market /

Phase I/II

Hepatitis C / Melanoma, multiple myeloma and

renal-cell carcinoma

PEG-arginine

deiminase

Phase I Hepatocellular carcinoma

3.2 Polymer – drug conjugate

Polymer-drug conjugation has been explored so far mainly as a means of targeted drug-delivery for

anti-cancer drugs. Most of the anti-cancer polymer-drug conjugates designed relies on the EPR

effect for passive targeting. Although extracellular drug-delivery can account for some anti-cancer

activity, a main concept behind polymer-drug conjugation is that of lysosomotropic and

endosomotropic drug delivery, that is, the liberation of the drug inside lysosomes and endosomes,

respectively.

Polymer-drug conjugates mechanism of action is based on two main aspects: EPR-mediated

targeting and endocellular drug-delivery through the endocytic pathway. After intravenous

administration of the conjugate, the increased leakiness of the tumour angiogenic vasculature would

lead to a preferential accumulation of the drug in the tumour interstitium, by the EPR effect (a and

b). The addition of cell specific targeting ligands (as in the case of HPMA copolymer-doxorubicin-

galactosamine, see below) could increase the targeting effect. B. After arrival in the tumour tissue,

the molecule would be internalized either by fluid-phase pinocytosis, non-specific receptor-

mediated pinocytosis or ligand-receptor docking. Lysosomal proteases (such as cathepsin B, which

is more expressed in tumoural cells) or the decrease in pH inside endosomes/lysosomes would lead

to either the cleavage of the polymer-drug linker or the polymer itself (as in the case of PGA-

paclitaxel, see below), releasing the drug inside the cell. Such a system of delivery could, in theory,

bypass certain resistance mechanisms, namely those associated with membrane efflux pumps as in

the case with MRP (multidrug resistant protein) and p-glycoprotein. Note that if the polymeric

carrier is non-biodegradable, its size must be limited in order to assure renal elimination and

preventing polymer-associated unwanted toxic effects (8).

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Fig 4: Targeted drug delivery mechanism using polymers (8)

Table 2: Some examples of widely used polymer-drug conjugates

Polymer-drug conjugates

Compound name Status Indications

HPMA copolymer-doxorubicin Phase II Various cancers, particularly lung and

breast cancer

HPMA copolymer-doxorubicin-

galactosamine

Phase I/II Particularly hepatocellular carcinoma

HPMA copolymer-

camptothecin

Phase I Various cancers

HPMA copolymer-paclitaxel Phase I Various cancers

HPMA copolymer-carboplatin

palatinate

Phase I/II Various cancers

HPMA copolymer-DACH-

platinate

Phase I/II Various cancers

PGA-paclitaxel Phase III Various cancers, particularly non-small

cell lung cancer; ovarian cancer

PGA-camptothecin Phase I/II Various cancers

Dextran-doxorubicin Phase I Various cancers

Modified dextran-camptothecin Phase I Various cancers

PEG-camptothecin Phase II Various cancers

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The conformations & structures of polymers are of real concern in order to design desirable

dosage form. This also increase bioavailability as well as efficiency of the drug encapsulated

or conjugated. New polymeric architectures that could provide interesting possibilities for

polymer conjugation. Their advantages include a more defined chemical composition,

tailored surface multivalency, providing more possibilities for conjugation, and a defined

three dimensional architecture (7).

Fig 5: General shapes of polymers (9)

4. IMPORTANCE OF RADIATION TECHNIQUES IN POLYMERIZATION

Ionizing radiation can be used for understanding mechanism of polymerization reaction as

well as for initiation of the polymerization process. Some of the advantages of the radiation

initiated polymerization over conventional methods are:

(i) Absence of foreign matter, like initiator, catalyst, etc., (ii) polymerization at low

temperature or in solid state, (iii) rate of the initiation step can easily be controlled by varying

dose rate and (iv) the initiating radicals can be produced uniformly by γ-irradiation. The

kinetics of polymerization of a variety of monomers was extensively studied which led to

better understanding of the mechanism of polymerization reactions. Some of the extensive

advanced applications are –

1) Radiation synthesis of polyaniline

2) Metal nanoparticles in hydrogel matrix

3) Hydrogel resins for removal of toxic metals from aqueous waste

4) Superabsorbents

5) Solid/liquid phase extraction of radionuclei (10)

4.1 Types of radiations

Radiation is energy given off by matter in the form of high speed rays or particles. All matter

is composed of atoms. These atoms constantly seek a strong, stable state. As they convert

from an unstable to stable form they release excess atomic energy in the form of radiation.

There are four types of radiation released from atoms; alpha, beta, gamma and neutron

radiation.

Alpha particles are highly charged and the heaviest of the nuclear radiations. Because of

their size and weight they are unable to travel very far and have a limited ability penetrate.

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They cannot travel more than four to seven inches in the air and can be stopped by a sheet of

paper or skin. They can be a hazard if they are inhaled or swallowed.

Beta particles are smaller and travel faster than alpha particles. They can travel several feet

in the air and are able to penetrate skin, though they do not usually penetrate deep enough to

reach vital organs. They can be stopped by a thin sheet of metal or plastic or a block of wood.

Gamma rays are not particles, but waves of radioactive energy. They travel much further

and have more penetrating power than either alpha or beta particles. They can travel as much

as a mile in open air and it takes several feet of concrete or several inches of a dense material

such as lead to block them.

Neutron radiation occurs when nuclear particles collide with other materials. Neutrons have

an exceptional ability to penetrate other materials and are extremely hazardous. Fortunately,

this type of radiation is generally only found in a nuclear power plant where it is shielded by

steel, concrete and several feet of water (11).

Fig 6: Penetration of radiation particles (11)

4.2 Application of radiation technique in biomedical aspects

New advancements & improvements have already been seen in the biomedical & clinical

aspects as far as the radiation technique & polymerization is concerned. As a matter of fact

radiation induced polymerization is being used in new drug development now a days.

4.2.1 Radiation induced controlled drug release from polymer hydrogels

Thermoresponsive hydrogels have recently become more attractive in the biomedical field;

its use included controlled drug delivery, (12,13), immobilized-enzyme reactors,(14,15,16)

and separation processes.(17,18,19,20) Poly(N isopropylacrylamide) (PNIPA) is a typical

one. This hydrogel swells in water or aqueous solution below the lower critical solution

temperature (LCST) and shrinks above LCST.(21,22,23,24,25,26) Its copolymer hydrogels

are often used in drug delivery and medicine concentration. But the drug release of difficult

dissoluble medicine is not so effective. Linear P(N-vinylpyrrolidone) (PVP) has good

physiological inertia and compatibility. PVP has the ability to bind reversibly to various

molecules (dyes, metals, and some polymers) by forming association

complexes.(27,28,29,30) Therefore, by introducing a 1-vinyl-2-pyrrolidone (NVP)-based

structure into a polymer hydrogel, which is thermoresponsive in a proper temperature range,

the reversible binding ability of PVP has been used together with the thermoresponsive

behavior to control the interaction of various biological molecules with the derivative

hydrogels. For preparation of NIPA Homopolymers & copolymers, gamma irradiation at a

fixed dose rate i.e. 1 KGy/h has been used (31).

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4.2.2 Ionizing radiation synthesis of ultra clean, sterile hydrogels as delivery device

The use of high energy radiation for the production of hydrogels has been proposed as a

methodology for the obtainment of biocompatible matrix materials that can incorporate and

release in a controlled fashion a wide variety of active ingredients. Irradiation of water

solutions of hydrophilic polymers (polyacrylates, polyvinyl pyrrolidone, polyvinyl alcohol,

polypeptides, etc.), with no use of initiators, catalysts or low molecular weight crosslinking

agents, leads to the production of material devices that can show a benign toxicological

profile (32).

At the same time, being hydrogels produced via a non thermally activated process, process

temperatures can be very low, even sub-ambient, therefore in situ incorporation of heat

sensitive or volatile actives in the hydrogel is possible (33). Newer developments of this

research are aimed to the production responsive hydrogels systems acting as smart cages,

where smart delivery of an active ingredient is triggered by changes of pH, applied electric

voltage, oxidising/reducing molecules, etc. Simultaneous sterilizations of materials can be

achieved.

4.2.3 Ionizing radiation induced Conjugated polymers/hydrogel nano-composites for

novel sensing functions

Conductive polymers offer unique physical, chemical and electronic properties, which make

them attractive as active components of ‘plastic electronics’, such as polymer light-emitting

diodes, field effect transistors, sensors, etc. Limitations on their processability and poor

biocompatibility have been overcome with a two step process: a dispersion polymerization

assisted by a suitable polymeric stabilizer, followed by gelification of the water dispersion,

induced by high energy radiation crosslinking of the stabilizer. Conductive polymer

nanoparticles are incorporated into a hydrogel matrix exhibiting interesting, and sometimes

unique, electrochemical, electric and optical properties (34,35,36), such as, for example,

fluorescence signals that change in intensity at the pH variance (37).

Fig 7: Hydrogel & conjugated polymer property (38)

4.2.4 Gamma irradiation based advanced multitherapeutic polymer drug development

Gamma irradiation has been used now as a unique technique for development of polymeric

male injectable contraceptive which acts a potential anti HIV drug and Benign Prostatic

Hyperplasia (BPH) treating agent.

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4.2.4.1 Reversible male injectable contraceptive

RISUG® (Reversible Inhibition of Sperm Under Guidance), a novel injectable male

contraceptive, is a viscous mixture of a copolymer Styrene Maleic Anhydride (SMA) &

Dimethylsulphoxide (DMSO) in 1:2 ratio (60mg of SMA in 120µl of DMSO). RISUG® is

injected into male vas deferens by a no-scalpel one shot injection method. Inside the lumen of

vas deferens, RISUG® forms a net like structure & the polyelectrolyte mosaic of charges on

the surface of RISUG® disturbs the surface charge of sperms resulting into acrosomal

breakage & release of acrosin & hyaluronidase. One shot of injection guarantees minimum 10

years of infertility & the process is reversible. For preparation, Styrene and maleic anhydride

monomer, after rigorous purification, are taken in a 1:1 ratio (20 ml styrene and 30 g maleic

anhydride). Ethyl acetate is added to the styrene and maleic anhydride mixture and N2 gas

purged into the glass bottles. Polymerization is done by gamma irradiation (0.3 Gy/s at 37°C

with a total dosage of 2.4 Gy) which is followed by precipitation with petroleum ether and

soxhlet distillation using 1, 2‐dichloroethane and distilled water, respectively. Monomers are

removed meticulously. The SMA obtained is purified, powdered and stored in stoppered

sterile glass tubes. The production of RISUG® is carried out in IIT Kharagpur in lab scale

and being upscaled in two different manufacturing set-ups.

4.2.4.2 Treatment of Benign Prostatic Hyperplasia

RISUG® can be used as a self designed drug delivery system for prostate. When RISUG® is

introduced in vas lumen, it acts as spermicidal. Along with this, RISUG® particles get

encapsulated by the phospholipids coming from the sperm debris. Here the peristaltic

movement of the vas deferens helps in the encapsulation procedure. Sulphur group from

DMSO gets tagged with the formed liposome & as prostate has got great affinity towards

sulphur groups, this whole nanoliposome traverses towards prostate. A classically used drug,

finasteride, can be tagged along with this nanoliposome to deliver into the prostate in order to

treat Benign Prostatic Hyperplasia (BPH).

Fig 8: Mechanism of treatment of BPH by RISUG (39.Guha SK et. al. 2010)

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4.2.4.3 Anti-HIV action of polymer drug

In addition to contraception, RISUG® has also shown to possess antimicrobial activity. The

research has proven that RISUG® possesses potent antimicrobial activity againsta number of

microorganisms such as Candida albicans, Pseudomonas aeruginosa, Staphylococcus

aureus, Escherichia coli, and Neisseria gonococci.The viruses are more susceptible to its

antimicrobial action than the vegetative form of bacteria such as Staphylococcus and

Pseudomonas.The drug has shown to possess anti-HIV activity due to its electrical charge

effect.

RISUG® serves its anti-HIV effect both in male & female. After coming in contact with

body fluids, RISUG® gets converted into by products like Styrene Maleic Acid (SMAAC) &

mandelic acid which are thought to be having entry inhibitory action against HIV infection.

The possible mechanisms of action of these two by products are; interaction with gp120 &

thereby preventing binding to CD4T cells & competitive binding with the viral glycoprotein

– cell surface glyocosaminoiglycan Heparan Sulphate (HS) interaction.

4.2.5 Local polymeric cancer chemotherapy

Cancer drugs can cause enormous toxicity; therefore, the opportunity to deliver them locally

creates the possibility of improving both the safety and efficacy of cancer chemotherapy. The

physical addition of a polymer to a cancer therapeutic has the advantage of enhancing the

benefit of surgery while minimizing the systemic toxicity that is usually associated with

standard drug treatments. The drug itself becomes more effective when placed next to, and

delivered directly to, its targeted tissue and much higher local drug concentrations can be

achieved compared to traditional approaches. Novel polymers such as polyanhydrides were

designed and have been utilized for this purpose (40) . These polymers, in the form of wafers,

have been used to locally deliver chemotherapeutic drugs such as carmustine (BCNU) to treat

brain cancer (41) . In these patients, the surgeon resects as much of the tumor as possible at

the time of the operation and then places small polymer drug wafers at the surface of the

brain in the tumor resection cavity . The drug is slowly released from these wafers for

approximately three weeks to destroy any remaining tumor. Because the drug is delivered

locally, rather than systemically, harmful side effects that normally occur are minimized. One

clinical trial showed that after 2 years, 31% of the patients treated were alive whereas only

6% of patients receiving standard brain tumor therapies survived (42) . This approach was

approved in 1996 by the U.S. Food and Drug Administration for patients with recurrent

glioblastoma, the first new brain cancer therapy approved in over 20 years. In 2003, the FDA

approval was extended to include initial surgery for malignant glioma based on two

additional randomized prospective studies that demonstrated improved survival and safety

(43) . Studies have also reported benefit for experimental brain metastases (44) and invasive

pituitary adenomas (45) . Local delivery of chemotherapeutics from long- lasting implantable

lipid formulations to spinal fluid has also been used clinically to treat carcinomatous

meningitis (46).

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Fig 9: Polymeric wafer drug delivery in glioblastoma (47. Marsha A Moses et.al. 2003)

4.2.6 Radiation induced polymeric preparation of established anti-HIV drug

Indinavir sulfate is a potent inhibitor of HIV protease which is widely used in the treatment of

AIDS and prescribed in combination with other protease inhibitors, nucleoside analogs, or

reverse transcriptase inhibitors (48) (Deeksetal.,1997). It is rapidly absorbed following oral

administration. Its narrow therapeutic window and poor systemic bioavailability create a risk

of adverse effects. Hence, some slow drug delivery devices are required for its delivery. It has

been reported that drug administration through polymer based drug delivery system improves

its pharmacokinetics and pharmacodynamic profile (49) (Chiappetta etal, 2009).

Keeping in view the gel forming nature of psyllium polysaccharide and radiation formation

of hydrogels, in the present study an attempt has been made to develop the psyllium and

binary monomer mixture of Acrylamide (AAm) and 2-Acrylamido-2-methylpropane sulfonic

acid (AMPSA) based hydrogels by a radiation method meant for slow drug delivery

applications.

Synthesis of hydrogels was carried out by a radiation induced graft copolymerization method.

The copolymerization was carried out in test tube with stoppers by mixing the psyllium with

solution of both monomers (AAm and AMPSA) prepared in10ml distilled water. First,

definite amount of both the monomers was dissolved in10 ml water taken in test tube and

then psyllium was added slowly with continuous stirring. There action system was irradiated

in the 60Co gamma chamber at a fixed total radiation dose in the presence of air in the

solution in test tube (50).

4.2.7 Radiation induced hydrogel based drug delivery system

Preparation of hydrogel-based drug product involves either cross-linking of linear polymers

or simultaneous polymerization of monofunctional monomers and cross-linking with

polyfunctional monomers (51,52). Further, the mechanical strength of poorly cross-linked

hydrogels can be adequately enhanced by various methods (53). Polymers from natural,

synthetic or semi-synthetic sources can be used for synthesizing hydrogels. Usually,

polymers containing hydroxyl, amine, amide, ether, carboxylate and sulfonate as functional

groups in their side chains are used.

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Fig 10: Schematic diagram representing hydrogel based drug delivery system (54.

Gupta P et.al 2002)

5. CONCLUSION

Far new approach has recently been developed in radiation chemistry, connected with photo-,

ultrasonic or glow discharge reactions, all of which are still in academic interests. Far deep

consideration has recently been paid by a new kind of analysis, for instance, for very thin

layer or for very short time. Prof. A. Charlesby (55) introduced a pulsed NMR technique for

studying radiation effects in macromolecules.

The above cited developments is by no means exhaustive and there are a number new results

and applications emerging in using ionizing radiation in modifying, upgrading and shaping

polymeric materials. Developments in source technologies, material handling systems,

formulation of new polymeric receipes and innovative approaches will continue to bring new

radiation treated products into the market.

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