聚乙二醇-b-聚（γ-丁内酯）嵌段共聚物的可控合成及其在药物控释中的应用

Biodegradable amphiphilic block copolymers have great advantages in the field of drug controlled release system. Poly(γ-butyrolactone) has great potential for drug deliver due to its excellent biocompatibility and rapid degradation rate. Moreover, the degradation products of poly(γ-butyrolactone) will not accumulate in the body and do not cause non-specific inflammatory response. However, it's hard to prepare poly(γ-butyrolactone) based amphiphilic block copolymers by ring-opening polymerization under common condition. Recently, homopolymerization of γ-butyrolactone has been successfully achieved with novel catalysts which laid the foundation for the synthesis of amphiphilic block copolymers. This project intends to prepare a series of poly(ethylene glycol)-poly(γ-butyrolactone) block copolymers by using organic phosphazene base catalyst. The relationship between structure and properties of poly(ethylene glycol)-poly(γ-butyrolactone) block copolymers was systematically investigated, and the drug-loaded micelles with excellent comprehensive properties were screened out. The selected drug-loaded micelles were tested by in vitro cell and model animal experiments to investigate the active targeting, EPR effects and therapy effect of drug-loaded micelles. This project will provide a new type of polymeric micelle drug carries. These micelles will provide new ideas for the design of highly effective anticancer drug delivery system.

生物可降解两亲性嵌段共聚物在药物控释领域具有极大的优越性。聚（γ-丁内酯）具有生物相容性优异、降解速率快、降解产物不在体内积累以及无非特异性炎症反应等特点，其在药物载体领域具有巨大的潜力。然而，受限于γ-丁内酯五元环的稳定性，在通常条件下难以通过开环聚合制备基于聚（γ-丁内酯）的两亲性嵌段共聚物。近期，借助新型催化剂成功实现了γ-丁内酯的均聚为两亲性嵌段共聚物的合成奠定了基础。本项目拟采用有机磷腈碱催化合成一系列聚乙二醇-b-聚（γ-丁内酯）嵌段共聚物。系统研究聚乙二醇-b-聚（γ-丁内酯）嵌段共聚物结构与性能之间的关系，并筛选综合性能优异的嵌段共聚物载药胶束。将所筛选纳米载药胶束进行体外细胞实验和动物试验，并详细考察载药胶束的靶向性、EPR效应和肿瘤治疗效果。本项目将提供一类新型聚合物胶束载体材料，为高效抗癌药物传输系统的设计提供新的思路。

聚（4-羟基丁酸酯）（P4HB）是目前唯一一种被美国食品药物监督管理局（FDA）批准的聚羟基脂肪酸酯（PHA）材料。本课题采用有机磷腈碱催化实现了高分子量P4HB的合成，该化学合成法避免了传统生物发酵技术生产成本高、产率低的缺点，为其在医疗领域中的应用奠定了基础。目前，美国Tepha公司研发的基于生物可降解P4HB的可吸收缝合线及疝修补片等产品已在临床上获得使用，故而P4HB成为了目前引人注目的研究热点之一。然而，研究人员对P4HB优异临床表现的内在机制仍未能完全阐明。此外，积极拓展P4HB在其他医疗领域的应用也具有十分重要的意义。本项目以P4HB为基体拓展其在医疗领域的应用，并对其相关机制进行研究：（1）通过双乳液-溶剂挥发法制备多孔P4HB微球，并研究其颅骨修复能力，体外和体内实验表明无干细胞或生长因子负载的前提下P4HB多孔微球仍可有效增强其骨修复性能；（2）通过静电纺丝技术制备了P4HB微米纤维膜并探索其在真皮支架领域的应用前景，研究发现P4HB多孔纤维膜作为真皮支架可极大的避免传统真皮支架的挛缩现象；（3）针对P4HB多孔纤维膜无抗菌性能和止血效果差的缺点，通过掺杂纳米氧化锌和聚乙二醇组分，提高其杀菌、抗污和止血功能，以满足高性能敷料的临床需求。体外和体内研究表明此类敷料可有效灭杀细菌，同时仍具有优异的止血性能。上述研究成果在ACS Applied Bio Materials、Journal of Materials Chemistry B和Colloids and Surfaces B: Biointerfaces等国际期刊上发表学术论文3篇，申请相关发明专利3项。