多层次智能药物传输体系的制备及其逆转多药耐药性

Multidrug resistance (MDR) of tumor cells is one of the leading causes that induce the failure of malignancy chemotherapy, and has thus become the most urgent problem to be solved in the oncology treatment. The encapsulation and controlled delivery of antitumor drugs with intelligent drug delivery platforms is one kind of novel idea to overcome the MDR of tumor cells. Inspired from the tumor tissular and intracellular microenvironments, this project is to prepare two kinds of shell-detachable drug delivery systems through the "Schiff base" reaction between aldehyde group in block copolymer and amino group on the surface of drug-loaded nanogel against the MDR of tumor cells. The multi-level intelligent drug delivery systems exhibit tumor targeting, and the drug-loaded nanogel as the core of nanocarrier shows the capabilities of enhanced tumor tissue penetration and cell endocytosis, and intracellular microenvironment triggered drug release. It aims to reverse the MDR of tumor cells and treat the advanced drug resistance tumors through the "on-demand" release and synergistic effect of monoclonal antibody, broad-spectrum antineoplastic and P-glycoprotein inhibitor. The implementation of this project will provide the experimental and theoretical foundations for the research and development of smart drug delivery system with clinical value for overcoming MDR of tumor cells.

肿瘤细胞多药耐药性是恶性肿瘤临床化学治疗失败的主要原因之一，已经成为肿瘤治疗中亟待解决的问题。通过智能药物传输体系负载和控制释放抗肿瘤药物是克服肿瘤细胞多药耐药性的一种新思路。本项目针对肿瘤细胞多药耐药性，从肿瘤组织和细胞内微环境出发，拟通过嵌段共聚物上的醛基与载药纳米凝胶表面上的氨基的"席夫碱"反应，制备两类外壳可脱离的药物传输体系。该多层次智能药物传输体系具有肿瘤靶向性，其载药纳米凝胶内核具有增强组织渗透、提高细胞内吞以及细胞内微环境响应性释放的能力，期望通过单克隆抗体、广谱抗肿瘤药物和P-糖蛋白抑制剂的"按需"释放和协同作用逆转肿瘤细胞多药耐药性，从而治疗晚期耐药性肿瘤。本项目的实施将为研制可逆转肿瘤细胞多药耐药性的具有临床应用价值的智能药物传输体系提供实验和理论基础。

目前，肿瘤渗透能力差及多药耐药性的产生是恶性肿瘤临床化学治疗失败的主要原因之一。为了解决上述问题，本项目以肿瘤组织和细胞的特殊微环境为基础设计并制备了一系列pH响应性、还原响应性的智能高分子纳米药物载体，以增强药物在肿瘤组织的渗透、提高肿瘤细胞摄取并实现细胞内高选择性药物释放。同时，通过多种药物间的协同作用达到抑制耐药肿瘤细胞生长的目的。系统的体外和体内实验证实了本项目所开发的智能高分子纳米载体提高了治疗效果，本项目已完成了预定的研究目标。在本项目的资助下，我们在国际知名学术期刊上发表论文22篇，申请中国发明专利7项，其中授权3项。