多级响应聚多肽-聚乙二醇胶体粒子的可控组装及在可视化药物传输中的应用研究

The variations of tumor microenvironments provide a new avenue to fabricate stimuli-responsive drug carriers, improve targeting ability and therapeutic efficacy. Colloidal particles composed of polymers have been widely used for drug delivery, which has attached great attention from scientists. Herein, we focus on the assembly of multistaged responsive, highly targeted polypeptide-poly(ethylene glycol) drug delivery systems and investigate the effect of the polypeptide composition and length on particle structure, size, stability, and surface chemistry. Based on these research, we will conclude the influence of the tunable physicochemical properties of the drug carriers on their biological behaviors. The multistaged responsiveness and targeting ability will be optimized via simulating the differences of biological microenvironments, tumor sites, and intracellular microenvironments for controlled anti-cancer drug release at designed sites. In addition, molecular imaging technology (e.g., fluorescence, optoacoustic, and magnetic resonance imaging) will be utilized for visual and trackable chemotherapy. The aim of this project is to engineer polypeptide-poly(ethylene glycol) drug carriers with high targeting and controlled release ability to decrease the side effect of anti-cancer drugs and increase the drug delivery efficacy.

肿瘤微环境的变化为构筑具有刺激响应性的药物载体、提高载体的靶向性和治疗效果提供了新思路；利用高分子组装的胶体体系已被广泛地应用于药物传输，是目前肿瘤诊疗的研究热点。本项目瞄准具有分级响应性和高靶向性的聚多肽-聚乙二醇药物载体，考察聚多肽的组成和链长对载体的组装结构、尺寸、稳定性、表面化学性质的影响，获得载体物理化学性质的调控对其与生物体系相互作用的规律。通过模拟正常生理环境、肿瘤部位、肿瘤细胞内微环境的差异，优化载体的分级响应性能和靶向功能，实现可控、定点地释放抗癌药物，并利用多模式分子影像技术（荧光、光声、核磁共振成像等），达到对肿瘤的可视化靶向化疗。本项目的目标是构筑集靶向性高、药物可控释放于一体的聚多肽-聚乙二醇药物载体，降低抗癌药物的副作用并提高给药效率。

本项目利用聚多肽和聚乙二醇作为主要构筑基元，通过自组装和模板法等策略构筑了功能高分子纳米载体，并探究了在药物递送中的应用。考察了组装基元的种类和比例对纳米载体的尺寸、稳定性、表面化学性质的影响，通过使用pH、氧化还原敏感的化学键调控了纳米载体的刺激响应性。重点研究了纳米载体的物理化学性质变化对其与生物体系相互作用的规律，构筑的聚乙二醇纳米载体能够克服体内的加速血液清除现象，载体表面修饰靶向分子可以有效提高载体在肿瘤部位的富集和肿瘤细胞的内吞作用。对纳米载体进行药物负载，探索了在肿瘤化疗、光疗、免疫治疗、多模式联合治疗方面的应用，并利用分子影像技术（荧光、核磁共振成像等），实现了肿瘤的可视化治疗。本研究旨在发展新方法构筑功能性聚多肽-聚乙二醇纳米载体，获取纳米-生物相互作用的机制和规律，为提高药物递送效率提供新思路。