抗肿瘤纳米药物载体的构建及其免疫逃逸抑制巨噬细胞吞噬机制

The innate immune system, known as the nonspecific immune system and the first line of defense, is an important subsystem of the overall immune system that comprises the cells and mechanisms that defend the host from infection by other organisms. Macrophages evolve to engulf and clear invading nanoparticles, which hampers delivery of therapeutics and imaging agents. Some diseased cells, however, can proliferate and metabolize under the human immune function, indicating there is wide immunologic escape in the human body which can help diseased cells escape from the host immune recognition and attack. In allusion to the host related clearance mechanism of nanovehicles, the project is planning to design and prepare macrophage phagocytosis-resisting and specific recognition nanovehicles. According to the mechanism of immunologic escape and the specific tumour microenvironment, we use controllable active polymerization and self-assembly technology to synthesize the polymers that possess the properties of immunologic escape, high targeting and multi-targeting sites. By introducing the effective dose of immunologic escape molecule (CD47), phenylboronic acid molecules with specific recognition, the project will study the effect of the carrier structure on tumor cell recognition and macrophage phagocytosis, and further explore the influence of the surface properties of the nanovehicles on their immunological effect to obtain the basic law of the anticancer vehicles prepared. This project will choose liver tumor as an object and build animal model to study the distribution, recognition and anticancer efficacy of nanovehicles in vivo. The program can systematically reveal the anti-tumor mechanism of nanocarriers from the molecule, cell and whole hierarchy levels, which will provide the helpful information for tumor therapy. Additionally, the program does not only obtain a new kind of anticancer drug vehicle with avoiding macrophage phagocytosis, but also offers important experiment data and scientific basis for the development of anti-tumor drug formulation and the new treatment method.

人体免疫系统是人类抵御疾病最重要的防线，但某些疾病细胞在人体免疫功能的作用下能够逃避机体免疫识别和攻击。针对纳米载体易被人体清除这一难题，依据免疫逃逸机制和肿瘤微环境生物学特征，本项目通过聚合物的分子设计、可控活性聚合和纳米组装技术等设计理念和方法，拟构建抑制巨噬细胞吞噬和响应肿瘤微环境的纳米载体；通过引入有效剂量的免疫逃逸分子-CD47和识别基团，系统研究纳米材料结构与尺度因素对抑制巨噬细胞吞噬和响应肿瘤微环境的影响；进一步研究纳米材料表面的理化性质与其免疫学效应的关系，探寻抗肿瘤载体材料设计的基本规律；建立肝癌动物模型，研究纳米材料进入体内的靶细胞效果和可能的副作用。从分子、细胞和整体层次上系统揭示纳米载体材料的作用机制。新型抗肿瘤药物载体一旦研制成功，不但避免载体在人体中被快速清除的发生，还可为全新、安全、方便肿瘤治疗药物的制剂开发和治疗新方法的探索提供重要的实验数据和科学依据。

为了实现将长循环和靶向肿瘤等功能的协同，提高药物在肿瘤部位的富集和摄取，本研究依据肿瘤局部的微环境生物学信息，设计与构筑新型抗肿瘤纳米药物载体。通过分子聚合分别合成了基于具有免疫逃逸功能化聚合物和靶向肿瘤细胞的聚合物，进一步运用组装技术，构筑了具有可拆卸的递送体系，通过多种体内成像技术，观察纳米粒在动物体内的富集及代谢过程。结果表明，纳米粒表面的免疫逃逸分子增加载体体内的循环时间；肿瘤部位弱酸性微环境可诱导载体的解离，激活靶向功能，提高了纳米粒在肿瘤部位的富集和细胞对纳米粒的摄取。在生理条件下，药物释放量较少，而在弱酸性(pH 5.4)条件下，药物释放量达增加。纳米粒在小鼠体内的药代动力学成像发现纳米粒5 min即能在肿瘤部位大量富集，且在肿瘤的截留时间长达24 h。所构筑药物递送体系实现了长循环、靶向性和多模拟态成像等多功能特性，为新型多功能肿瘤的诊断与治疗系统的开展设计提供了一条新的思路。