Synthesis And Properties Of Functional Biodegradable Carbonates Copolymers

Biodegradable polymers are the kind of polymer materials that can be degraded under the action of microbial enzyme or chemical decomposition. Biodegradable polymers can be divided into natural and synthetic polymers. They have a wide variety of potential biomedical applications such as medical devices, drug/gene delivery systems and tissue engineering because of their good biocompatibility and degradability. Drug controlled release system is one of the most important applications of biodegradable polymer materials and has attracted wide attention. Aliphatic polycarbonates is one of the most important biodegradable polymers, which could be easily modified by copolymerization or functionalization method. In chapter1of this thesis, recent developments of biodegradable polymers and their application in controlled release system are briefly reviewed, with the emphasis on the functionalization of aliphatic polycarbonates.In chapter2, ring-opening copolymerization of5-allyloxy-1,3-dioxan-2-one (ATMC) with ?-caprolactone (CL) was successfully performed for the first time in bulk at140?using stannous octanoate as the catalyst. The resulting novel poly(ATMC-co-CL) were characterized by1H-NMR, GPC, DSC, X-ray diffraction and static contact angle method.. The copolymer compositions and properties could be adjusted by varying the monomer feed ratio, and a random repeat unit distribution on the basis of the Fox equation. In vitro cytotoxicity studies using MTT assay demonstrated that the copolymer had low cytotoxicity compared to PCL homopolymer. Degradation in the presence of pseudomonas lipase showed that only CL-richer copolymer would be susceptible to significantly degrade. And there was almost no molecular weight changes occurred during degradation, in agreement with a surface erosion mechanism shown by SEM analysis.In chapter3, novel biodegradable amphiphilic block-graft copolymers based on methoxy poly(ethylene glycol)-b-(polycarbonates-g-polycarbonates)(mPEG-b-(PATMC-g-PATMC)) were synthesized successfully for controlled release of doxorubicin (DOX). Backbone block copolymer, mPEG-b-PATMC was synthesized in bulk catalyzed by immobilized porcine pancreas lipase (IPPL). Then, mPEG-b-PATMC-O, the allyl epoxidation product of mPEG-b-PATMC, was further grafted by PATMC itself also using IPPL as the catalyst. The copolymers were characterized by1H-NMR and GPC results showed narrow molecular weight distributions. Stable micelle solutions could be prepared by dialysis method, while a monomodal and narrow size distribution could be obtained. TEM observation showed the micelles dispersed in spherical shape with nano-size before and after DOX loading. Compared with the block copolymers, the grafted structure could enhance the interaction of polymer chains with drug molecules and improve the drug-loading capacity and entrapment efficiency. Furthermore, the amphiphilic block-graft copolymers mPEG-b-(PATMC-g-PATMC) had low cytotoxicity and more sustained drug release behavior.In chapter4, novel reduction-sensitive core-cross-linked mPEG-polycarbonates were synthesized successfully for controlled release of DOX. The disulfide-bond-containing tetra acryloyl carbonate (4AC) was synthesized by Michael-addition of cystamine hydrochloride with one kind of six-membered cyclic carbonate, acryloyl carbonate (AC). Then the biodegradable amphiphilic copolymers mPEG-b-P(DTC-co-4AC) were synthesized by enzymatic method. The structures of the obtained monomer and copolymers were confirmed by'H-NMR. The in vitro DOX release behaviors indicated that cross-linking of the micelle cores resulted in a low drug release and this process was greatly accelerated by adding DTT solution with comparable concentrations to intracellular levels in HeLa cells. Confocal laser scanning microscopy (CLSM) results showed that DOX-loaded cross-linked micelles could be internalized by the cells and then release DOX into the nuclei of HeLa cells.In chapter5, temperature and reduction dual sensitive core-cross-linked PNIPAAm-b-P(DTC-co-4AC) was further synthesized by enzymatic ring-opening polymerization. The polymeric micelles had a monomodal and narrow size distribution, while the LCST was about39.8?. DOX was loaded into the micelles as a model drug. The in vitro release studies showed that a rapid drug release could be obtained either at higher temperatures or under reductive conditions. Intracellular DOX release into the nuclei of HeLa cells could be observed by CLSM. MTT assays indicated that DOX-loaded micelles exhibited high anti-tumor activity with IC50(inhibitory concentration to produce50%cell death) of6.3mg/mL, while blank micelles were practically non-toxic up to a tested concentration of800mg/L In chapter6, novel amphiphilic polycarbonates-graft-doxorubicin (mPEG-b-P(ATMC-co-DTC)-g-DOX) prodrugs were successfully developed for the first time. DOX was conjugated to the backbone block copolymers via pH-sensitive hydrazone bond. Particle size of mPEG-b-P(ATMC-co-DTC)-g-DOX micelles was determined by DLS and TEM, which showed a monomodal and narrow size distribution. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and polycarbonates. The in vitro cytotoxicity of polymeric prodrugs was tested using MTT assay. CLSM observations revealed that mPEG-b-P(ATMC-co-DTC)-g-DOX prodrugs could efficiently deliver and release DOX into the nuclei of HeLa cells.