Stimuli-responsive Copolymeric Micelles For Anti-cancer Drug Delivery

Over the past decades, significant advances have been made in the development of amphiphilic copolymeric micelles for drug delivery. Copolymeric micelles can improve solubility of hydrophobic anti-cancer drugs and facilitate preferential accumulation at tumor sites via the enhanced permeability and retention (EPR) effect. Furthermore, stimuli-responsive copolymeric micelles have received much attention due to the fact that they can respond to stimuli from the tumor microenvironment and release anti-cancer drugs promptly. In the first chapter of this thesis, development of drug delivery system was briefly reviewed, with the emphasis on the application of stimuli-responsive copolymeric micelles for anti-cancer drug delivery.In chapter 2, amphiphilic block copolymer mPEG-b-PAC was synthesized in toluene using IPPL as the catalyst. Then redox-responsive core-crosslinked mPEG-b-PAC-SS-was synthesized using cystamine as a crosslinker. Transmission electron microscopy (TEM) observation showed that both uncrosslinked and crosslinked micelles dispersed in spherical shape with nano-size before and after doxombicin (DOX) loading. As compared to mPEG-b-PAC, core-crosslinked mPEG-b-PAC-SS-showed better colloidal stability and higher drug loading capacity. Moreover, the in vitro release studies showed that DOX was readily released from mPEG-b-PAC-SS1-under reductive condition similar to intracellular environment, while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.In chapter 3, novel amphiphilic copolymer based on redox-responsive shell-sheddable mPEG-SS-P(2AC-co-MAC) was successfully for efficient delivery and release of DOX to cancer cells. mPEG-b-PMAC was also synthesized by the same enzymatic methods for comparison. The resulting copolymers could self-assemble to form nano-sized micelles in aqueous solution by dialysis method and showed low cellular cytotoxicity. As compared to mPEG-b-PMAC, CLSM showed an accelerated release of mPEG-SS-P(2AC-co-MAC) in intracellular environment and MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.In chapter 4, a novel thymine-functionalized six-membered cyclic carbonate monomer (TAC) was synthesized by the Michael-addition reaction between thymine and AC. The corresponding functional amphiphilic block copolymer mPEG-b-PTAC was further successfully synthesized by ring-opening polymerization using IPPL as the catalyst and mPEG as the macroinitiator. Meanwhile, mPEG-b-P(TAC-co-DTC) and mPEG-b-PDTC were also synthesized by the same enzymatic methods for comparison on different TAC contents. All the amphiphilic block copolymers could self-assemble to form nano-sized micelles in aqueous solution. TEM observation showed that the micelles dispersed in spherical shape with nano-size before and after MTX loading.1H-NMR and FTIR results confirmed the successful formation of multiple hydrogen-bonding interactions between exposed thymine groups of hydrophobic PTAC segments and 2,6-diaminopyridine (DAP) groups of MTX molecules, which resulting in the higher drug loading capacity and the pH-sensitive drug release behavior. MTT assays also indicated lower toxicity of copolymer but higher potent cytotoxic activity of MTX-loaded copolymer against HeLa cells.In chapter 5, thymine-functionalized redox-responsive copolymer T-PEG-T/mPEG-SS-PDTC was successfully synthesized for controlled release of MTX. The structures of T-VEG-T and mPEG-SS-PDTC were confirmed by 1H-NMR. mPEG-SS-PDTC could self-assemble to form nano-sized micelles in aqueous solution, while T-PEG-T could form multiple hydrogen-bonding interactions with MTX molecules. The in vitro release studies displayed dual redox and pH-sensitive behaviors. MTT assays indicated lower toxicity of T-PEG-TmPEG-SS-PDTC and higher potent cytotoxic activity of MTX-loaded copolymer against HeLa cells.In chapter 6, novel amphiphilic copolymer on the basis of pH-responsive mPEG-dop/Chol-PBA was successfully synthesized for efficient delivery and controlled release of DOX. The resulting copolymers, characterized by'H-NMR, could self-assemble to form nano-sized micelles in aqueous solution by dialysis method and showed low cellular cytotoxicity. The in vitro release studies showed that DOX could be readily released at low pH condition. Moreover, CLSM showed enhanced cellular uptake via cholesterol moieties and rapid release at low pH condition, while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.