双酶响应性两亲线形-树枝状嵌段共聚物研究

Enzyme-responsive polymers have great potential in applications of biomedical field such as drug delivery, diagnostics and tissue engineering, etc due to their advantages of biocompatibility and high selectivity. The design and synthesis of dual enzyme-responsive polymers will endow enzyme-responsive materials with more fascinating features and further broaden their bioapplications. In this project, a series of dual enzyme-responsive amphiphilic linear-dendritic block copolymers with linear poly(N-vinylpyrrolidone)(PVP) or poly(hydroxyethyl L-glutamine) chain will be synthesized via a combination of reversible addition-fragmentation chain transfer (RAFT) polymerization, click chemistry and a supramolecular strategy. The self-assembling assemblies of these amphiphilic copolymers are able to undergo enzyme-triggered disintegration in the presence of cathepsin B and phosphatase, known to be overexpressed in certain tumor tissues. The self-assembly behavior in aqueous solution, enzyme-responsive property and biocompatibility of these copolymers will be improved and optimized by modifying the enzyme-responsive sites, composition and generation of the dendrons, and the molecular weight of linear polymeric chains. The enzyme-responsive drug release behavior and in vitro cell cytotoxicity of these copolymers will be investigated in order to reveal concerning relationship between structure and properties of the copolymers. The research results of this project will provide theoretical direction and valuable information for development of new anticancer drug delivery vehicles.

酶响应性高分子体系具有良好的生物相容性和高度的选择性，在药物传输、疾病诊治、组织工程等生物医学领域有着重要的应用前景。设计合成能对两种酶具有响应性的高分子，可望获得更适合体内生理环境的药物载体。基于此，本项目拟结合可逆加成-断裂链转移（RAFT）自由基聚合、点击化学和静电相互作用自组装等技术，设计合成对在肿瘤组织中两种高表达酶（组织蛋白酶B和磷酸酶）有响应的、以聚（N-乙烯基吡咯烷酮）或聚（羟乙基-L-谷氨酰胺）为线形链的两亲性线形-树形杂化嵌段共聚物。通过变化酶响应基团的位置、树枝化基元的组成和代数，以及控制线形链的分子量等手段，优化此类共聚物的自组装、酶响应性和生物相容性。研究其酶响应性药物释放性能和细胞毒性，探讨其结构-性能关系。为高效低毒低成本的新型抗癌药物载体的设计、合成和应用提供理论依据。

酶响应性聚合物因具有优异的生物相容性和高度的选择性，可望成为靶向药物释放系统的理想药物载体。本项目将蛋白酶响应性官能团引入到线形-树枝状嵌段共聚物（LDBCs）的不同位置，设计合成了多个系列线形链为可被酶降解的线形-树枝状嵌段共聚物（LDBCs）、酶响应位点为树枝化基元构筑单位的LDBCs、酶响应位点在树枝化基元和线形链连接处并具有酶和pH双重响应性能的LDBCs、具有酶和温度双重响应性的LDBCs、哑铃形双酶响应性超两亲分子、具有温度、pH和酶响应性的超两亲分子；对这些两亲性共聚物和超两亲分子的溶液自组装性能、环境刺激响应性解组装性能、体外细胞毒性和对模型药物的包载和释放行为进行了系统研究。结果表明，酶响应基团的位置、树枝化基元的组成和代数、线形链的分子量对共聚物的性能均有影响。具有相同酶响应性官能团的LDBCs，与酶响应位点在树枝化基元上的LDBCs相比，酶响应位点在树枝化基元和线形链连接处的LDBCs在水溶液中自组装形成的聚集体在酶的作用下解组装更快，所包载药物的释放速率也更快，药物的释放量也增加；随着亲脂性树枝化基元代数的增加，LDBCs在水溶液中形成的聚集体稳定性增加，酶解速率减慢，所包载药物的释放速率也较慢；酶的浓度对LDBCs形成的聚集体的解组装也有影响，酶浓度越高，LDBCs聚集体解组装越快，释放速率和释放量越大。双酶响应性和多重刺激响应性的共聚物或超两亲分子在双酶或多重刺激（如酶和pH）条件下，对所包载模型药物的释放速率比单酶或单一刺激条件下的药物释放速率快。项目研究结果为深入探讨酶响应性聚合物及其超两亲分子的结构与性能关系和新型智能型靶向药物载体的研制和应用提供了实验依据。