Design Of Efficient Drug Delivery System Based On The Interactions Between Functional Copolymer Micelles And Drugs

In order to reduce side effects of conventional cancer treatment,tremendous effort has been directed to the development of controlled drug release system.The biodegradable copolymer micelle,one of the most important drug delivery carriers,has received significant attentions due to its special nano-structure with a hydrophobic core and hydrophilic shell.Several strategies have been investigated to enhance its application potential,such as crosslinking method for improving micelle stability,combining targeting ligands to improve the anti-tumor effects,controlled drug release responsive to tumor microenvironments?such as pH and redox potential?.Furthermore,the introduction of non-covalent interactions between drugs and carriers,such as hydrogen bond interaction and electrostatic interaction,could enhance the drug loading capacity,but also provide an effective approach for controlled drug-release due to their environmental sensitivity.In general,amphiphilic copolymers could self-assemble to form micelles in aqueous solution,while biodegradable aliphatic polycarbonates and polyethylene glycol?PEG?have been used as hydrophobic segment and hydrophilic segment respectively.In the first chapter of this thesis,the development and application of copolymer micelles in controlled drug release system were reviewed,with the emphasis on the functional aliphatic polycarbonates and the interactions between drugs and carriers.In chapter 2,carboxyl-modified copolymer mPEG-b-PATMC-g-SCH2COOH based on unmodified mPEG-b-PATMC was successfully synthesized for high-efficiency loading and controlled release of doxorubicin?DOX?.Both the carboxyl-modified and unmodified copolymers could self-assemble to form nano-sized micelles in aqueous solution and showed very low cellular cytotoxicity.Compared with the unmodified copolymer,the carboxyl-modified structure in mPEG-b-PATMC-g-SCH2COOH could markedly enhance the drug-loading capacity and entrapment efficiency via the electrostatic interaction.The in vitro release studies showed more sustained drug release behavior of mPEG-b-PATMC-g-SCH2COOH without an initial burst,which could be further adjusted by the conditions of ionic strength and pH.The cell environments indicated efficient cellular uptake of DOX delivered by mPEG-b-PATMC-g-SCH2COOH and showed potent cytotoxic activity against HeLa cells.In chapter 3,four different kinds of pendent mercaptan acids modified copolymers mPEG-b-PATMC-g-SRCOOH(R=-CH2-,-CH2CH2-,-?CH₂?₁₀-and-CH?COOH?CH2-)were successfully synthesized by 'thiol-ene' click reactions based on mPEG-b-PATMC.All carboxyl-modified amphiphlic copolymers could self-assemble into negatively-charged nano-micelles in aqueous solution and showed low cellular cytotoxicity against COS7 cells or HeLa cells.The positively-charged DOX could effectively load into copolymer micelles via synergistic hydrophobic and electrostatic interactions.Especially in the case of mPEG-b-PATMC-g-S?CH₂?₁₀COOH micelles,the suitable hydrophobility and charge density were not only beneficial to improve the DOX-loading efficiency,they were also good for obtaining lower CMC value,smaller particle size and potent cytotoxic activity against cancer cells.The well designed mPEG-b-PATMC-g-SRCOOH copolymers would be expected as a potentially applicable drug delivery system.In chapter 4,pH and redox dual-responsive mixed micelles were prepared by blending carboxyl-modified copolymer mPEG-b-PATMC-g-S?CH₂?₁₀COOH with mPEG-SS-PATMC copolymer containing redox-sensitive disulfide bonds.DOX could effectively be loaded into mixed micelles via synergistic hydrophobic and electrostatic interactions.DLS and TEM measurements showed the mixed micelles dispersed in spherical shape with nano-size before and after DOX loading.The in vitro release studies showed sustained drug release behavior without an initial burst,which could be accelerated under low pH and reducing condition.Confocal laser scanning microscopy?CLSM?and MTT assays further demonstrated efficient cellular uptake of DOX delivered by the dual-responsive mixed micelles and potent cytotoxic activity against HeLa cells.In chapter 5,novel thymine and carboxyl dual-functional block copolymer mPEG-b-Poly(TAC-co-ATMC-g-S?CH₂?₁₀COOH)was designed and synthesized for efficient co-delivery of two different kinds of chemotherapeutic drugs,DOX and MTX.This biodegradable amphiphilic copolymer could self-assemble into negatively-charged nanomicelles with higher micelle stability and lower hemolysis ratio.Based on the additional electrostatic interactions and complementary multiple hydrogen-bonding interactions between drug and carriers,DOX and MTX could be simultaneously loaded in the mPEG-b-Poly(TAC-co-ATMC-g-S?CH₂?₁₀COOH)with high-efficiency loading without interference with each other.DOX/MTX co-loaded micelles displayed sustained drug release behavior which could be accelerated in an intracellular low pH environment.Cell experiments also indicated efficient cellular uptake of DOX and MTX together and enhanced synergistic antitumor efficacy of DOX/MTX co-loaded micelles based on mPEG-b-Poly(TAC-co-ATMC-g-S?CH₂?₁₀COOH),which might have important potential in clinical implications for efficient combination chemotherapy.In chapter 6,amine-modified copolymer mPEG-b-PATMC-g-SCH2CH2NH2 was synthesized by 'thiol-ene' click reaction based on copolymer mPEG-b-PATMC,which could self-assemble into positively-charged nano-micelles PN.Core-crosslinked copolymer micelles PNS were further prepared by 'thiol-ene' click reaction with 1,8-dimercaptooctane,while CD44-targeted core-crosslinked copolymer micelles HA-PNS were successfully obtained by electrostatic adsorption of Hyaluronic Acid?HA?on PNS.Meanwhile,an acid-sensitive DOX derivative?DAD?was prepared by modifying DOX with 2,3-dimethylmaleic anhydride,which could reduce DOX-induced toxic side effects against normal cells.PN,PNS and HA-PNS showed low cellular cytotoxicity and high DAD loading capacity via the electrostatic interactions.The DAD-loaded micelles could hinder the release of DOX in physiological environment?pH=7.4?and efficiently release DOX in acid environment.Based on overexpression of CD44 in MCF7 cells,much more efficient cellular uptake of HA-PNS could be observed by CLSM.MTT assays also exhibited highly potent cytotoxic activity against MCF-7 cells.All the results suggested that the targeted core-crosslinked copolymer micelles might have good potentials as a novel drug delivery system with higher drug loading capacity and micelle stability,as well as enhanced antitumor efficacy with reduced adverse drug effects.