PDMAEMA基共聚物的多重响应和多重相转变行为及其应用

Gene therapy is one of the most promising treatments for both congenital genetic disorders and severe acquired diseases, such as cancers, cardiovascular diseases. The clinical applications of gene therapy, however, are restricted by shortage of safe, efficient gene delivery technology. In the past decade, polymer-based gene delivery systems have attracted great attention due to many advantages including low immune responses, improved safety, enabling repeated uses, convenient preparation and high efficiency. In this project, series copolymers based on poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) with multi-responsiveness and multi-phase transition behaviors will be designed and prepared to be potential gene delivery carries. Combined the experimental method with molecular simulation, the relations between copolymer structure and the stimuli-responsive property, the interactions between copolymer and DNA, and the biodegradation rate under different conditions will be investigated. The copolymer/DNA complexes will be formed, transferred and unwrapped by the tunable multistimuli-responsive properties and the multi-phase transition behaviors. To be expected, systems with low cell toxicity and high transfection efficiency will be constructed. The structure information at molecular level will provide the theoretical basis and micromechanism of genetic transfection.

基因治疗可为先天性遗传疾病和严重后天获得性疾病的治疗提供有效途径，高分子非病毒基因载体因其低免疫反应、可运载任何尺寸的基因、制备简单方便、基因转染效率高等优点而受到青睐。本项目以基因转染为应用背景，设计并合成系列生物可降解的新型基于聚甲基丙烯酸-N,N-甲氨基乙酯(PDMAEMA)的聚合物基因载体材料，该聚合物对环境的变化具有多重响应特性，在溶液中聚集体呈现多级结构转变。本项目采用实验观察与计算机分子模拟相结合的方法，研究聚合物结构与其环境响应特性、聚集态结构转变的关系，观察其与DNA的复合物的形成、微观结构和解构过程，探索利用该聚合物的多重环境响应性进行DNA压缩、输运和释放过程的调控，构建低细胞毒性和高转染效率基因载体体系，为基因转染过程和机理研究提供分子水平的理论基础和指导。

高分子基因/药物载体因其低免疫反应、可运载任何尺寸的基因、制备简单方便、基因转染/药物释放可控等优点而受到青睐。本项目以基因转染/药物控释为应用背景，设计并合成系列生物可降解的新型聚甲基丙烯酸-N,N-甲氨基乙酯(PDMAEMA)基聚合物，详细研究其多重响应和聚集体的多级结构转变特性及其微观机理，探索其与DNA的复合物的形成、微观结构和结构过程等。具体为：在实验方面，设计并合成了多种具有多重响应的PDMAEMA基共聚物，如PDMAEMA-PSBMA，PDMAEMA-PMeO2MA，PDMAEMA-PNIPAM；研究了具有多重响应性共聚物的溶液聚集形态及其调控机理；并将具有多重响应相转变的聚合物应用于基因转染、药物控释、响应性乳液等方面。在计算机模拟方面，模拟了响应性聚合物的溶液聚集行为，并与实验结果吻合；比较了不同结构亲疏水改性的阳离子聚合物DNA压缩性能的影响，为高性能聚合物基因载体的设计提供指导；建立了可用于描述二元共聚物凝胶的温度敏感溶胀行为和体积相变行为的模型，为响应性共聚高分子凝胶的应用研究提供理论依据。目前已在国际知名学术刊物上发表研究论文16篇，论文均被SCI收录；在国内外学术会议上交流论文3篇；申请并获授权发明专利1项。参加本项目主要研究工作的研究生中有2人获博士学位，3人获硕士学位。