Y型糖核异臂两亲性脂肪族聚酯/聚乙二醇星形聚合物的酶促合成及其拓扑结构与性能的关系

Many amphiphilic copolymers based on aliphatic polyesters such as poly(ε-caprolactone) (PCL) and poly(p-dioxanone) (PPDO) and poly(ethylene glycol) (PEG), which is one of the most widely used hydrophilic polymers have been synthesized as hydrophobic drug carriers. Because these amphiphilic copolymers can self assemble into nanometric micelles in aqueous solution, they can escape from reticuloendothelial system (RES). It was well known that the topological structure has great relationship with the morphology, stability and the size of micelle, which will directly decide the drug capacity, drug release and in vivo circulation. Recently many literatures demonstrated that star polymers have advantages in self-assembled morphology control as well as drug release compared to the linear polymer. .In this project,Y type 3-miktoarm star copolymers will be synthesized by enzyme in which PCL, PPDO and PEG as well as their copolymers are arms, alkyl α-D-glucopyranoside is a core. Due to the high regioselectivity and stereoselectivity of enzyme catalysis, no protection and de-protection procedures will be needed. Firstly, sugar containing PPDO (sugar-P) will be synthesized by enzyme catalyzed ring-opening polymerization (EROP) of p-dioxanone (PDO) specifically initiated by the 6-primary alcohol of alkyl α-D-glucopyranoside. For the attachment of the other arms at the chosen site of the sugar core, it was necessary to end-cap the terminal hydroxyl group of PPDO. The terminal hydroxyl group of PPDO will be transformed into an acylating group by reacted with vinyl methacrylate using Novozyme-435 as a catalyst. Secondly, in the presence of lipase, methoxy-PEG will initiate ROP of ε-CL or PDO to obtain aliphatic polyester/PEG copolymers. The terminal hydroxyl of the obtained copolymers will be changed to a carboxyl group (AP-PEG-COOH) easily in the presence of succinic anhydride (SA), 4-(dimethylamino) pyridine (DMAP) and triethylamine (TEA). Finally, the esterfication between 2[R]-, 4[R]- secondary alcohol of alkyl α-D-glucopyranoside with PEG-COOH or AP-PEG-COOH will occur due to the high regioselectivity of enzyme catalysis. Due to the solubility difference and micro-phase separation, these star copolymers can self assembly into aggregates with different morphology. The introduction of sugar moiety can endow star polymers having specifically cell recognition function. In this project the relationship between the topological structure of the obtained star polymers and properties as well as their self assembly behavior will be investigated in detail. This project will laid the theoretical basis for the usage of this novel star copolymer in drug delivery systems. Besides this, this project will broaden the enzyme catalysis application and provide a new way for synthesis of medical-used polymers without metal residues.

两亲性星形聚合物由于其独特的拓扑结构在自组装形貌控制以及作为药物释载体方面比线性聚合物更具有优势。本项目拟以聚对二氧环己酮（PPDO）、聚乙二醇（PEG）、聚（ε-己内酯）（PCL）及其它们的嵌段共聚物为臂，以烷基吡喃葡糖苷为核，利用酶催化的高度立体及区域选择性，无需保护及脱保护步骤就可以合成出具有Y型结构、可完全生物降解、生物相容的两亲性糖核脂肪族聚酯/聚乙二醇星形聚合物。利用两亲性星形共聚物溶解性的差别及微相分离可以获得不同形貌的纳米聚集体。由于糖核的引入，此类星形聚合物形成的纳米载药胶束还具有特异性细胞识别的功能。本项目将详细研究所合成的星形聚合物的拓扑结构与其性能、自组装行为的内在联系，为该类糖核异臂星形聚合物在药物控释领域的应用奠定理论基础。通过对酶促合成星形聚合物的研究，将拓宽酶催化在合成高分子中的应用，并为获得无金属残留的、更适应生物医用的星形聚合物提供新方法。

本项目以聚对二氧环己酮（PPDO）、聚（ε-己内酯）（PCL）、聚乙二醇（PEG）以及及其共聚物为臂，以烷基吡喃葡糖苷为核，利用酶催化以及酶化学结合方法制备了一系列具有优良生物相容性及可完全生物降解的两亲性糖核脂肪族聚酯/聚乙二醇星形聚合物。采用酶催化及酶促化学结合的方法，无需保护及脱保护步骤，方便可控地合成了具有精确分子结构的星形聚合物。通过调控星形聚合物的拓扑结构，可以获得具有不同临界胶束浓度、胶束粒径以及形貌的纳米聚集体。此外，研究中还发现具有不同拓扑结构的星形聚合物在药物负载效率、药物释放速率以及杀伤癌细胞方面存在差异。此外，本项目还进一步将研究体系拓展到其他具有刺激响应性的不同拓扑结构两亲性共聚物的制备及性能研究上，发现Y型聚合物、H型聚合物以及三嵌段共聚物自组装行为以及刺激响应性表现出明显不同，揭示出两亲性共聚物的拓扑结构与其自组装行为及其药物释放性能之间的内在联系。本项目为这类两亲性糖核脂肪族聚酯/聚乙二醇星形聚合物在在药物释放领域的应用打下良好的基础，同时也拓宽了酶催化在合成高分子中的应用，为获得更适应生物医用的星形聚合物提供了新方法。.本项目已经完成既定的研究目标，目前已经在Chemical Communications、ACS Sustainable Chemistry& Engineering、Colloid and Surface B: Biointerfaces、Polymer等主流刊物上发表SCI收录论文18篇，其中第一标注13篇，第二标注3篇，第三标注2篇。申请中国发明专利1项并获授权。培养博士2人（其中在读1人），硕士3人。

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