Synthesis Of Amphiphilic Random Polymer-Drug Conjugates And Self-Assembly Of Their Targeting Micelles

Synthesis of polymer-drug conjugates and fabrication of conjugate-based micelles or nanoparticles have been an intense field of research, since these systems offer numerous advantages compared to conventional low-molecular-weight drugs including controlled drug release and improved targeting ability. In this thesis, a chemo-enzymatic synthetic strategy was employed to prepare polymer-drug conjugates. Moreover, the resulting amphiphilic random polymer-drug conjugates were successfully self-assembled to fabricate a series of micelle-type assemblies. Their in vitro release behaviors and targeting abilities to HepG2 liver carcinoma cell were further investigated.The enzymatic selective synthesis of polymerizable drug monomers including multifunctional drug and optically active drug monomers was studied. Three multifunctional drugs including acyclovir, ribavirin and azacitidine were chosen as substrates, and divinyl dicarboxylates with different chain lengths were used as acylating agents. By enzymatic chemoselective or regioselective transesterification in organic medium, a series of polymerizable drug monomers with different chain lengths were prepared. Choosing racemic ketoprofen as substrate and vinyl acetate as acylating agent, optically active ketoprofen polymerizable monomer was obtained by enzymatic stereoselective hydrolysis resolution of ketoprofen vinyl ester prepared using chemical method. Moreover, such influence factors of enzymatic synthesis as enzyme sources, reaction media, water content and so on were investigated.A strategy combining enzymatic selective synthesis with radical polymerization was developed to fabricate polymer-drug conjugates. Radical homopolymerization of the drug (acyclovir, ribavirin, azacitidine) polymerizable monomers prepared by enzymatic selective transesterification offered a series of polymer-drug conjugates with high drug content. By radical copolymerization of these drug polymerizable monomers with liver-targeting sugar (galactose, lactose) polymerizable monomers, a series of amphiphilic random polymer-drug conjugates with potential liver-targeting function were prepared. Besides sugar vinyl esters, two monomethoxyl PEG methylacrylate with different PEG molecular weight (PEG350, PEG1000) were synthesized and chosen as comonomers. A series of amphiphilic random polymer-drug conjugates with different ketoprofen contents and PEG chain lengths were obtained by copolymerization of optically active ketoprofen vinyl ester with the PEG comonomers.Self-assembly of the resulting amphiphilic random polymer-drug conjugates in aqueous phase was successfully achieved to fabricate a series of conjugate-based micelle-type assemblies. Polymeric micelles with diameter of 208 nm or 135 nm were respectively prepared by self-assembly of the amphiphilic random polymer-ribavirn conjugates containing galactose or lactose. Assembly abilities of these conjugates were studied, and influence of conjugate structure and assembly conditions on their self-assembly behaviors was investigated. By self-assembly of the amphiphilic random polymer-azacitidine conjugate containing galactose, microdisk-type assemblies with radium from 250 nm to 500 nm and thickness of 16 nm were obtained. Assembly ability of the conjugate was investigated, and assembly mechanism was preliminary discussed. A series of size-controllable spheric micro- or nano-particles with radii from 70 nm to 1.1μm were fabricated by self-assembly of the amphiphilic random polymer-ketoprofen conjugates containing PEG, and influence of conjugate structure including ketoprofen content and PEG chain length on size of the assemblies was investigated.In vitro release behaviors and targeting abilities of the polymer-drug conjugates or conjugate-based micelles containing sugar were studied. The results showed that the small molecular drugs could be slowed released, and the release rate was relative to the pH value of incubation medium, relative length of the linker binding drug to polymer main chain and conjugate composition. The polymer-drug conjugates and conjugate-based micelles containing glactose or lactose showed evident targeting function to HepG2 liver carcinoma cell, and cellar internalization of the drugs could be achieved by galactose- or lactose-mediated endocytosis process.