Synthesis of polyphosphazenes containing different side groups and their application in drug control

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Polyphosphazenes (PPHOSs) are hybrid inorganic-organic class of polymers with widerange of properties from rubber like behavior to potential for biomedical applications such as tissue engineering and drug delivery applications.PPHOSs have inorganic backbone and organic side groups of various types and these side groups determine the properties of PPHOSs.The simplest example is polydichlorophosphazene (PDCP), which has nitrogen and phosphorous attached with alternative single and double bonds and has two reactivechlorines attached on each repeating unit.The macromolecular substitution of these chlorines with suitable organic nucleophiles determines the properties of final polymer.An infinite number of nucleophilic groups can be replaced over PDCP backbone and producepolymers of versatile range of properties.  Recently, many kinds of PPHOSs with different side groups were synthesized, which have ability to self-assemble into nanoparticles or blend with other kind of polymers to preparesuch material that can be used for drug delivery or tissue engineering applications.  In this regard, PPHOSs with different kind of side groups were synthesized and characterized by 1H-NMR, 31p-NMR and GPC.Depending upon the structure of synthesized polymers, their blending ability with other biocompatible polymers and abilityto self-assemble into nanoparticles were studied.The miscibility of synthesized polymerswith other biocompatible polymers was studied by FTIR and DSC.For drug releaseapplications, drug loaded microspheres, nanoparticles and nanofibers were fabricated andin vitro drug release kinetics was studied at physiological conditions.  Reductive responsive nano-vehicles have ability to deliver the anticancer drugs to theintracellular compartments.The purpose of this study was to develop reductive sensitivenano-carriers based on polyphosphazenes.Amphiphilic polyphosphazenes with hydrophilic reductive sensitive side group were synthesized and characterized.There ductive sensitive PEG (PEG-SS-NH2) was synthesized via two steps.In first step, PEGwas allowed to react with 4-nitrophenyl chloroformate (4NPC) to produce reactiveinter mediate.Then in second step, reactive intermediate was allowed to react withcystamine to prepare PEG-SS-NH2.The peaks at 7.36 ppm for-NH2, 4.41 ppm for-NHand 3.50 ppm for PEG repeating confirmed the synthesis of PEG-SS-NH2.Then for thesynthesis of poly[bis(D-phenylalanine methylate PEG-SS-amino) phosphazenes] (PDPPs)first PEG-SS-NH2 was grafted on PDCP backbone via macromolecular replacementreaction.Then D-phenylanine ester (DMPE) was allowed to react partially substituted PDCP.Finally, the successful synthesis of PDPPs was confirmed with 1H-NMR, 31p-NMRand GPC.The synthesized copolymers showed solvent dependent self-aggregation andform spherical micelles by using THF as co-organic solvent in dialysis method.Nile red isa fluorescent dye and at proper spectral conditions, it can be used to detect lipophilicmicro-environments by using fluorescent spectroscopy.CMC values for PDPPs was foundranging from 5.73 μg/mL to 11.24 μg/mL.CMC value depends on the combination ofhydrophilic and hydrophobic mole ratios.The CMC value can be changed by altering themole ratio of the hydrophilic and hydrophobic side groups.Micelles can encapsulate thehydrophobic drug such as CPT and IND.The obtained micelles were spherical in shapewith size ranging from ~37 nm to ~114 nm.In this study, CPT was selected as modelanticancer drug to evaluate the carrying and release ability of bioreducable PDPPs.In invitro release experiments, CPT loaded micelles release the 70% to 80% of the loaded CPTin the presence of reducing agent (DTT) within 15 hours.The results indicated that thesereductive sensitive amphiphilic polyphosphazenes may find an application as anticancerdrug carriers for safe drug delivery.
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