环境响应型自降解聚乙醛酸酯的设计、合成及其在基因及药物输送的应用研究

Recent years, polymers with good biocompatibility have attracted tremendous interest in the field of biology and medical science. Self-immolative polymers, a kind of polymers that could depolymerize from end to end via intramolecular cascade reactions trigged by external stimuli, maybe used as degradable polymers with high biocompatibility. Polyglyoxylate is one of the important self-immolative polymers, its degradation products are biocompatible and relatively low toxic. Despite it potential applications, there still lacks researches about the functionalization of its pendant groups. Herein, we designed several functionalized glyoxylate derivatives and its corresponding cationic self-immolative homopolymers. Click reaction could be used to prepare amphiphilic block polymers based on cationic polyglyoxylates and poly(ethyl glyoxylate). The cationic/amphiphilic polyglyoxylates would form nanocomposites with nucleic acid/drugs and demonstrate stimuli-responsive nucleic acid/drug releasing abilities. Their cargo loading properties and stimuli-triggered self-immolative properties will be studied. The carrying out of this project will provide theoretical and application foundations for the further development of self-immolative polyglyoxylates and benefit the research of high-efficacy and biocompatible polymers.

近年来，具有良好生物相容性的聚合物在生物及医学相关领域得到了极大的关注。自降解聚合物是一类可以在刺激下发生引发从“头”到“尾”的分子内串联反应继而产生解聚的聚合物，有望成为具有高度生物相容性的可降解高分子材料。聚乙醛酸酯是一种重要的自降解聚合物，其降解产物具有良好的生物相容性，然而目前对于其侧链功能化的研究仍然较少。本项目设计具有侧链官能团修饰的乙醛酸酯单体，聚合形成可自降解的阳离子型聚乙醛酸酯，同时利用点击反应制备基于阳离子型聚乙醛酸酯与聚乙醛酸乙酯的两亲性嵌段共聚物。并进一步将阳离子型聚乙醛酸酯和两亲性聚乙醛酸酯分别用于与核酸/药物分子形成纳米复合物，研究纳米复合物的包载性能以及刺激响应自降解能力，实现刺激响应性的核酸/药物分子释放，为聚乙醛酸酯这类自降解聚合物材料的进一步开发提供理论和应用研究的基础，促进高效、生物兼容的聚合物材料的研究和发展。

本研究设计了具有侧链官能团修饰的乙醛酸酯单体，考察了富马酸酯/异戊烯酸酯臭氧化、酒石酸酯裂解、二乙氧基乙酸乙酯脱保护、乙醇酸酯TEMPO氧化等多种方案，实验表明其中乙醇酸酯TEMPO氧化法可用于制备目标氨基取代的乙醛酸酯单体，其余路线均存在各样的问题。同时实验发现所获得的乙醛酸酯单体稳定性较差，存在自聚合的倾向，不利于规模化制备和存储。本项目同时也利用聚合后胺解修饰侧链的方法，制备并表征了具有N,N-二甲基乙二胺、二乙烯三胺、N,N,N-三甲基乙二胺结构的阳离子水溶性聚乙醛酸衍生物，通过MTT实验初步考察了这几种材料对细胞的毒性情况。考察了材料与pGFP形成纳米复合物的能力，并研究了对HeLa细胞、MCF-7细胞的转染作用。结果表明侧链修饰基团对聚乙醛酸衍生物的转染性能有巨大影响，N,N-二甲基乙二胺修饰的材料几乎无法实现pGFP的转染，而二乙烯三胺结构的衍生物则具有良好的pGFP转染作用和较低的细胞毒性，是一种具有潜力的生物相容性核酸输送载体。