Asian Research Thesis Index

Abstract

This work is concerned with synthesis of multiresponsive smart copolymer hybrid microgels and polymer drug conjugates. Work can be divided in to two parts. In first part, we have synthesized both cationic and anionic hybrid microgels. Cationic pure NIsopropylacrylamide and vinyl imidazole copolymer, P(NIPAM-co-VI), microgels with different amount of vinyl imidazole were synthesized by free radical emulsion polymerization. Then, the hybrid microgels, P(NIPAM-co-VI)-Ag, was prepared and their thermal and pH dual responsive properties were studied. Thermogravimetric analysis were also carried out for the amount of metal content, and a maximum content 51.8% was obtained for P(NIPAM-co-VI)-3-Ag. The pH and thermos-responsive behavior was also analyzed for surface plasmon resonance using uv-visible spectroscopy. All the hybrid microgels could be stably dispersed in water at a pH range from 3.0 to 9.3, which is favorable to use p(NIPAM-co-VI)-Ag as a catalyst in the reduction reaction of p-nitrophenol. The highest reaction rate constant (kapp) value 4.49×10-3 sec-1 was observed for p(NIPAM-co-VI)-3-Ag at pH 2.95. Reaction rate was dependent on pH of the medium and the content of 1-VI in the copolymer microgels. We have also prepared anionic copolymer microgels based on thermal NIPAM and pH sensitive MAA. In-situ reduction method was used to prepare silver and gold hybrid microgels at two different pH’s. The surface charge involved in the change of particle size, was confirmed by calculating zeta potential values at different pH’s using dynamic light scattering. The prepared hybrid microgels were used as a catalyst for the reduction of p-nitrophenol to p-aminophenol. Our results shows that the p(NIPAM-co-MAA)s-Au catalysts are more efficient as compared to p(NIPAM-co-MAA)s-Ag. In the second part, we have synthesized a novel redox-responsive polymer–drug conjugate (PDC) based on hydrophilic diblock copolymer covalently bonded with paclitaxel (PTX) by a disulfide linker, and evaluated it for intracellular drug delivery. The well-defined hydrophilic diblock copolymer, PEG-b-PHEMA, was synthesized via atom transfer radical polymerization of 2-(trimethylsilyloxyl)ethyl methacrylate (HEMA-TMS), using PEG-Br as a macroinitiator and CuBr/PMDETA as the catalytic system, followed by selectively hydrolyzing the trimethylsilane group to hydroxyl groups. Utilizing the hydroxyl groups as an active reaction site, paclitaxel was covalently conjugated onto the backbone of the diblock copolymer, with a disulfide linker as a spacer to bridge the copolymer and PTX, and the loading content of paclitaxel was 18.4 wt%. Due to the different solubility of segments in the polymer–drug conjugate, the amphiphilic PEG-b-P(HEMA-PTX) could self-assemble into spherical micelles in aqueous solution, with hydrophobic PTX as core and hydrophilic PEG chains as shell. The in vitro cytotoxicity experimental results shows that the diblock copolymer is biocompatible, with no obvious cytotoxicity, whereas the PEG-b-P(HEMA-PTX) conjugate showed glutathione-dependent cytotoxicity with higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated HeLa cells. We are convinced that polymer–drug conjugates based on disulfide linkers will be a promising platform for targeted intracellular controlled drug delivery in cancer therapy.

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