氟化修饰方法制备高效、安全的多功能高分子基因载体

Cationic polymers were widely used as non-viral gene vectors, however, transfection efficacy and cytotoxicity of these polymers are strongly associated, that is a high transfection efficacy is usually associated with a devastating toxicity. To achive high transfection efficacy at an extremely low nitrogen to phosphorus ratio is a key solution to this problem. In this proposal, we propose a fluorination strategy to improve the transfection efficacy of cationic polymers on a list of cells. Different fluorination routes are proposed to prepare fluorinated polymers and the structure-function rationships of these materials will be studied. The exact reason behind the high transfection efficacy of fluorinated polymers and the reason why fluorinated polymers can achive high efficacy at extremely low nitrogen to phosphorus ratios will be investigated. In addition, the in vivo transfection efficacy of these fluorinated polymers as well as the potential applications of 19F MRI to image the polymeric vectors during gene transfection will be evaluated. The aim of this project is to develop fluorination strategy as a promising method to prepare high efficient, biocompatible and multifunctional gene vectors.

阳离子高分子被广泛应用为非病毒类基因载体,但这类高分子载体转染效率与生物相容性之间通常存在"恶性"关联，即获得高转染效率的同时产生严重的细胞毒性。如何在低氮磷比（净正电荷）条件下获得高转染效率成为解决这一问题的关键。本项目提出了一种氟化修饰方法，能够在极低的氮磷比条件下在多种细胞中实现高效基因转染。项目拟探索不同氟化修饰方法改性常用阳离子高分子基因载体的可行性以及这类材料结构与功能之间的关系；探索氟化修饰提高阳离子高分子转染效率，降低氮磷比的机理；评估所制备载体的体内转染效率，并尝试能够在基因转染的同时实现对转染组织的19F MRI成像。通过本项目的研究，希望将氟化修饰发展成为一种制备高效、安全、多功能高分子基因载体的有效方法。

项目负责人发展了一类含氟高分子载体用于基因、蛋白质等生物分子的胞内递送，获得了一批高性能聚合物载体，丰富了现有高分子基因递送系统。研究过程中发现了含氟高分子在基因和蛋白质递送中独特的氟效应，并利用这种效应设计了一系列高效、低毒的高分子载体材料；阐明了氟元素在高分子核酸复合物的血清稳定性、细胞摄入、内涵体逃逸、胞内核酸释放等多个步骤中的重要作用；从低分子量聚合物出发，通过氟-氟相互作用等作为驱动力构筑了一系列兼具高效、低毒特点的超分子载体材料，一定程度上打破了阳离子聚合物载体在转染效率与细胞毒性之间普遍存在的恶性关联；通过材料库筛选的方法获得了高性能含氟高分子载体用于蛋白质胞内递送，并探索了含氟高分子作为载体在肿瘤基因和蛋白质治疗中的应用。项目负责人在Nat. Commun., Angew. Chem. Int. Ed., ACS Central Science等刊物以通讯作者发表论文33篇，申请、授权发明专利7项。受邀在Chem. Rev.发表专题综述Surface-engineered Dendrimers in Gene Delivery；受《高分子学报》邀请撰写了含氟高分子载体的特约专论。研究工作为高分子载体的设计提供了新思路和理论支持。