可靶向修饰的刺激响应性聚合物载体的设计与制备

The new generation of drug carriers based on polymer assemblies is being conceived with the main objectives of protecting the active molecules against degradation, reducing drug toxicity to healthy cells and controlling drug release in time and space, which have great application prospects. For these purpose, the carrier material of polymers should be endowed with multiple functions such as targeting and stimuli-responsive properties. Therefore, development of synthetic strategy for the functionalized polymers, exploration of the fabrication method for polymer carriers with controlled structures and investigation of their functions have great research values. In this project, we intend to develop a strategy to synthesize a series of new amphiphilic block copolymers and fabricate the functional polymer carriers. The targeting properties will be endowed to the copolymers by synthesis of hydrophilic blocks with the active end groups can efficiently link to the target molecules. The introducing of disulfide groups to the copolymers will give them stimuli-responsive properties by polymerization of monomers containing disulfide bond, or combination of RAFT-ATRP polymerization to obtain disulfide linkers. The self-assembly behaviors of these functional block copolymers in aqueous phase will be investigated intensively, focusing on the fabrication of the polymer assemblies with controlled size and morphologies. The targeting modification and stimuli-responsive properties of polymer assemblies will be systematically investigated to find the appropriate polymer carriers, which will be utilized to conjugate with the targeting antibody and loading the anticancer drug. Finally, we will attempt to explore their selectivity of targeting to cancer cells, the performances of intracellular drug release and over-all effect of anticancer in vitro. It is hoped that the implementation of this project will not only expand general strategy for the synthesis of functionalized polymers, but also opens a door to the versatile fabrication of the novel polymer carriers with multiple functions, which will have potential applications for anticancer research.

新一代聚合物纳米载体需具备可靶向修饰和可控释放有效成分的能力，从而实现向病灶组织的高效提送药物，并在降低药物对正常细胞的毒副作用的同时增强治疗效果, 具有广阔的应用前景。此类智能载体的构建与功能聚合物的结构紧密相关，因此设计合成功能聚合物，并探索载体结构的可控构建以及研究其功能性质具有重要的研究价值。本项目拟发展一种制备聚合物多功能化的有效方法，从而获得同时具有可靶向修饰及刺激响应性能的聚合物载体。拟合成含有可与靶向分子高效链接的功能基团以及双硫键基团的多功能化聚合物。研究此功能聚合物的自组装行为，探索制备具有尺寸、形貌可控的载体结构的最佳方法。研究聚合物组装结构可靶向修饰能力及刺激响应性能，并进行细胞内药物智能递送、控制释放行为的综合评估。本项目的成功实施，有望为制备具有靶向及控释功能的智能载体提供一条新途径。

一、新一代聚合物纳米载体材料需具备多功能化性质，如可靶向基团修饰及控释能力等，从而实现有效成分的定位定时高效递送。基于此理念，我们选取生物相容性聚乙二醇及胆固醇结构基元，以功能化RAFT试剂及单体的设计合成为出发点，通过RAFT聚合以及RAFT-ATRP聚合联用的方式合成了一系列含有呋喃官端基和还原响应性二硫键基团的功能化嵌段聚合物。结果表明此合成策略可实现了对聚合物结构、功能基团化学位置及含量的调控，为设计合成多功能化聚合物提供了一条新的思路。.二、聚合物的物理化学性质与其自组装行为、聚集体结构和性能之间存在密不可分的联系，探究其规律将为发展功能化聚合物纳米材料提供理论指导和实验基础。对此系列功能化聚合物进行系统研究后发现，含胆固醇刚性基元的聚合物体系在固相下具有不同程度的液晶相排列，调控其堆砌有序度可成功构建具有球状、纤维状、椭球状及圆球形囊泡状等多种形貌的纳米组装结构。同时，由于成液晶相排列的存在，组装体稳定性能提高，其还原响应性能亦可通过组装结构进行调控。.三、还原响应型载体材料具有细胞内释放有效成分的重要功能，而纳米材料表面的原位功能化修饰能力将进一步扩展此类载体材料的应用范围。基于本项目中合成的功能化聚合物具有呋喃官能团的特点，我们以外加还原试剂及荧光模型分子的方法，探究了聚合物及多种形貌组装体的还原响应性能以及表面修饰功能化基团的能力。结果表明，此系列聚合物均具有较为敏感的还原响应性能，聚合物的化学结构及组装体聚集态形貌是影响其性能的关键因素；同时，组装体表面均可高效地原位修饰多种功能化基团。细胞实验表明，组装体尺寸、形貌、表面功能化基团等因素综合影响其与细胞的相互作用。以上研究结果有望为发展靶向-刺激响应型药物载体材料提供一定的理论支撑。