Study On Synthesis Of Polyphosphazenes With Different Side Groups Containing N And O And Their Application As Drug Delivery Carriers

Polyphosphazenes(PPZ)belong to the family of polymers which are hybrid in nature containing an inorganic backbone of nitrogen and phosphorous and the attached side groups which are organic in nature.The backbone and bonds between phosphorous and side groups are hydrolytically sensitive and make the PPZ biodegradable and the resulting non-toxic degradable products make them biocompatible for various biological applications especially drug delivery.The starting material is"hexachlorocyclotriphosphazene(HCCP)" which polymerize into linear reactive intermediate "polydichlorophosphazene(PDCP)".PDCP can be further reacted with variety of organic groups to produce PPZ with diverse properties.The use of different side groups can produce PPZ with a range of properties from hydrophobic to hydrophilic,bio-stable to biodegradable and varying characteristics for drug delivery applications.The properties of PPZ can be further modified by being blend with other polymers which imparts interesting characteristics to PPZ blends.The synthesized PPZ are characterized by 1H NMR,31NMR,GPC and FTIR.Blending of PPZ are analyzed by TGA,DCS and SEM.PPZ are playing an important role in drug delivery applications especially in the delivery of anti-cancer drugs.These drugs have many disadvantages when they are used without any delivery system,and require high dosage quantities which result in non-specificity,toxicity to normal cells and fast renal clearance.PPZ provide a platform to develop many different drug carriers including microsphere,micelles,films,fibers,polymersomes and hydrogels which can carry the drugs in a much safe way to the specific sites and release the payload in a much sustained manner for longer time.For this reason synthesis of novel PPZ having different combinations of side groups with suitable properties is continued.In our research we used specific organic compounds which contain nitrogen and oxygen in their structures.N and O provide specific characteristics to the polyphosphazenes including better solubility and ability to blend with other polymers and they provide the point of attachment to the main chain of polyphosphazenes.1)Skin cancer is a serious problem in many countries and common methods of treatment have many drawbacks due to uncontrolled release drugs and repeated dosage patterns.The preparation of transdermal patches which can release the drug for long time could be a better choice.In our work,a novel biodegradable poly[(methyl 4-hydroxybenzoate)(4-hydroxybenzaldehyde)(diethylamino)phosphazene](PMHTP)was synthesized and characterized by 1H,31p NMR,DSC,GPC,and UV-Vis.spectroscopy.The prepared PMHTP was blended with PVP in different ratios and the most suitable blend(P3B3-3)was fabricated into micro/nanofibers by the electrospinning technique.The miscibility of the P3B3-3 was analyzed by DSC.Hydrolytic degradation studies of PMHTP and P3B3-3 films were carried out upto six weeks and molecular mass loss(detected by GPC)was studied.SEM analysis of degraded films showed the surface erosion,which is more vigorous in acidic conditions."Camptothecin",an anti-cancer drug was loaded in the prepared films and fibers and their in vitro comparative drug release behavior was observed.The prepared films and fibers could be suitable candidate to prepare long term patches for skin cancer therapy.2)Drug combination therapy is an emerging technology to treat the diseases like cancer which are still annoyance to human being.Combination of two or more drugs can deal with diseases in a better way.Various different techniques have been introduced which can deliver combination of drugs in a safe and more controlled manner.In our research,we prepared polyphosphazene based blend microspheres which can deliver two different drugs in a much sustained manner for long time."Acetamidophenol",commonly used drug was attached to the polyphosphazene main chain in different ratios along with glycine methyl ester toproduce drug-polymer conjugates(SUM-301,SUM-305 and SUM-306).SUM-305 and SUM-306 were then blended with PMMA in different ratios to fabricate the microspheres.The nature of PPZ used and ratio of PMMA in the blends affected the size and morphology of microspheres.The concentration of S5P-2 blend was also varied to produce microspheres with different size and morphology.These blend microspheres were hydrolytically degradable as indicated by the SEM images taken during hydrolytic degradation studies.Another anti-cancer drug "camptothecin" was loaded in these microspheres to fabricate dual-drug loaded microsphere.Furthermore,in vitro drug release behaviors of fabricated microspheres were also demonstrated,which showed that both drugs released in a sustained manner for 20 days.3)Drug delivery studies against different diseases are an important in biomedical applications.Diseases like "cancer" are very hazardous to mankind and need be treated very sensibly because drugs that are being used for its treatment can damage the healthy cells.So,there is demand for some safe carriers that can target the cancer cells without any damage to healthy cells.For this purpose,stimuli responsive materials are being used which can release drug on-demand and at accurate location.In our research,we synthesized three PPZ(SUM-401,SUM-402 and SUM-404)with different combinations of "Azo" and "MPEG"moieties which are hydrophilic in nature and soluble in almost all the commonly used solvents as well as in water.The synthesized PPZ were characterized by 1H,31P NMR,DSC,TGA and GPC.The presence of azo group in the polymer makes them responsive to UV-Vis which was determined by UV-Vis spectrophotometer by applying the UV and Visible light.Hydrolytic degradation studies were also performed in neutral and acidic conditions and molecular weight loss was determined by GPC.The PPZ produced different self-assembled nanostructures in THF and DMF which can respond to UV and pH and their self-assembled nanostructures were disturbed by applying UV and pH.Anti-cancer drugs"camptothecin" and "doxorubicin" were loaded on these nanostructures and their in vitro release behavior was observed at two different pH values.4)Colorectal cancer is another very serious type of cancer which still need be treated in proper way.5-FU is one of the most effective drugs for this cancer treatment but has many side effects in higher doses and still need some proper drug delivery system.We synthesized three PPZs(SM-10,SM-11 and SM-12)with different combinations of 4-hydroxybenzaldehyde and glycine ethyl ester.SM-11 and SM-12 were converted into microspheres by using oil-in-water emulsion method and "5-flourouracil(5-FU)" was loaded in these microspheres to study the in vitro release behavior of 5-FU.These microspheres showed a sustained release of 5-FU in both physiological and acidic medium upto 50 h.