Functional Biodegradable Polymeric Micelles For Efficient Delivery Of Doxorubicin

During the past decades significant advances have been made in the development of biodegradable polymeric materials for biomedical applications, especially in the field of drug delivery. Biodegradable polymeric micelles self-assembled from amphiphilic block copolymers have emerged as one of the most promising platforms for targeted and controlled anticancer drug delivery due to their good biocompatibility, in vivo degradability, and also several physico-and bio-chemical advantages, such as a core-shell structure with the hydrophobic core for efficient loading of poorly water soluble drugs, a layer of antifouling hydrophilic shells to warrant excellent colloidal stability and prolong drug circulation time as well as enhance permeability and retention (EPR) effect. In the first chapter of this thesis, developments of biodegradable polymers and drug delivery system were briefly reviewed, with the emphasis on the functional amphiphilic self-assembled polymeric micelles and novel strategies of carrier design for targeted and efficient cancer treatments.In chapter2, novel biodegradable amphiphilic copolymer based on reduction-sensitive core-crosslinked mPEG-b-PCL-b-PPEMA-SS-was successfully synthesized for efficient delivery and release of doxorubicin (DOX) to cancer cells. The resulting copolymers, characterized by1H-NMR and GPC, could self-assemble to form nano-sized micelles in aqueous solution by dialysis method and showed low cellular cytotoxicity. Transmission electron microscopy (TEM) observation showed that the micelles dispersed in spherical shape with nano-size before and after DOX loading. The in vitro release studies showed that DOX was readily released under reductive condition similar to intracellular environment. Furthermore, as compared to the uncrosslinked copolymers, much more efficient cellular uptake of mPEG-b-PCL-b-PPEMA-SS-with the existence of GSH could be observed by confocal laser scanning microscopy (CLSM), while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.In chapter3, novel biodegradable amphiphilic copolymer on the basis of reduction-sensitive layer-crosslinked mPEG-b-PPEMA-b-PCL-SS-was successfully synthesized. Both uncrosslinked and crosslinked block copolymers could self-assemble to form nano-sized micelles in aqueous solution and showed low cellular cytotoxicity. As compared to the uncrosslinked copolymers, CLSM showed much more efficient cellular uptake of mPEG-b-PPEMA-b-PCL-SS-and MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells. The in vitro release studies displayed a rapid drug release either in the presence of GSH or ALP, and much more rapid release in the presence of both GSH and ALP.In chapter4, novel phosphatidylcholine-modified amphiphilic block copolymer mPEG-b-P(MAC-co-DTC)-MPC was synthesized successfully for controlled release of DOX. The structures of the obtained monomer and copolymers were confirmed by 'H-NMR. mPEG-b-P(MAC-co-DTC)-MPC can self-assemble to micelles in aqueous solution, which showed low cytotoxicity, more sustained drug release behavior and good resistance to protein adsorption.In chapter5, novel biodegradable amphiphilic block copolymers based on folate-conjugated FA-PEG-b-P(MAC-co-DTC) was successfully synthesized for targeted and efficient delivery of DOX to cancer cells. The resulting copolymers could self-assemble to form nano-sized micelles in aqueous solution by dialysis method. TEM observation showed that the micelles dispersed in spherical shape with nano-size before and after DOX loading. Both the FA-conjugated and non-conjugated block copolymers showed low cellular cytotoxicity. Furthermore, as compared to the non-conjugated copolymers, much more efficient cellular uptake of the FA-conjugated copolymers via FA-receptor-mediated endocytosis could be observed by CLSM, while MTT assays also demonstrated highly potent cytotoxic activity against HeLa cells.In chapter6, novel biodegradable amphiphilic block copolymers FA-PEG/mPEG-b-P(MAC-co-DTC)-SS'-was successfully synthesized based on Chapter5. The resulting copolymers could self-assemble to form nano-sized micelles in aqueous solution and showed low cellular cytotoxicity. Compared with both uncrosslinked copolymers and non-conjugated copolymers, CLSM showed much more efficient cellular uptake of the FA-conjugated copolymers via FA-receptor-mediated endocytosis and an accelerated release in the presence of GSH. MTT assays also demonstrated highly potent cytotoxic activity of FA-PEG/mPEG-b-P(MAC-co-DTC)-SS-against HeLa cells.