响应性两亲小分子前药的设计、组装行为及抗肿瘤活性研究

Based on the drawback of the anticancer drug in the course of treatment, this project aims to construct a new type system of amphiphilic small molecule prodrugs with high drug loading content and the responsive release behavior in microenvironment of tumor. The main contents of the research are as follows: 1) The anticancer drug is conjugated with different biocompatible small molecules via chemical bonds, which are responsive to the microenvironment of tumor, such as disulfide bond, ester bond, hydrazone bond and so on. Besides, the hydrophilic and hydrophobic anticancer drugs are conjugated with each other through the above listed chemical bonds to obtain the amphiphilic small molecule prodrug. The water solubility, membrane permeability and assembly behavior of the as-synthesized amphiphilic small molecule prodrug are investigated, and the mechanism of self-assembly is explored. 2) The in vivo / in vitro drug release kinetics process and the environmentally responsive release behavior of the assemblies constructed by the as-synthesized small molecule prodrugs are invesigated. The sustained drug release mechanism is established, and the in vitro cytotoxicity and cell uptake of the assemblies are studied. 3) The antitumor effect of the assemblies constructed by small molecule prodrugs is studied. The assemblies with highly therapeutic effect are screened by investigating the distribution of the drug in the blood, organs and tumor tissue of the tumor-bearing mice combined with the corresponding tumor inhibition rate. The structure-activity relationship between the assembly and the antitumor efficiency is elucidated. This project can enrich the biological application of amphiphilic molecular assembly, broaden the research scope of colloid chemistry and pharmaceutics, and establish a new self-delivery system with high efficiency and responsive drug release in the microenvironment of tumor.

基于抗癌药物分子在治疗过程中存在的缺点，本项目拟构建一类兼具高载药量和肿瘤微环境响应性释药功能的新型两亲小分子前药体系。主要研究内容：1）利用不同性质的生物相容性小分子通过二硫键、酯键、腙键等肿瘤微环境响应性键修饰抗癌药物分子，或将亲水性和疏水性抗癌药物通过以上化学键直接键连，构建两亲性小分子前药体系；考察水溶性、透膜性及组装行为，探索自组装机制。2）研究小分子前药组装体的体内、体外释药动力学过程及环境响应性释药行为，建立药物缓释机制；考察其体外细胞毒性、细胞摄取行为。3）研究小分子前药组装体的抗肿瘤效果，通过药物在荷瘤小鼠血液、器官、肿瘤组织中的分布以及对肿瘤的抑制率筛选出具有高效治疗效果的组装体；找出组装体结构与抗肿瘤效果之间的构效关系。本项目可丰富两亲分子组装体的生物应用，拓宽胶体化学与药剂学的研究范围，建立一类新型、高效及具有肿瘤微环境响应性释药功能的药物自传递体系。

本项目主要针对抗肿瘤药物（化疗药、光敏剂、小分子抑制剂等）分子在临床应用过程中存在的缺陷，如水溶性差、溶解度低、毒副作用大等缺点，利用肿瘤微环境响应性化学键（酯键、二硫键等）合成了一系列两亲性小分子前药，通过透析、过柱进行纯化。利用核磁、质谱、红外光谱等技术确证了两亲小分子的成功合成。研究了这类分子的组装行为，组装体的体外细胞毒性、体内组织分布及体内药效学。由于药物基两亲小分子直接组装成纳米制剂，所以大大提高了载药量，显著降低了由于惰性材料引入的毒性；响应性键实现了载体在肿瘤处定点释放药物；靶头的接入使得载体具有主动靶向肿瘤细胞的功能。研究结果证明该类制剂对肿瘤细胞具有较强的毒性以及很好的体内抗肿瘤效果。同时，基于本项目资助我们合成了一系列药物-大分子接枝物，其可以在水溶液中直接组装成纳米粒，可以有效避免药物的突释；合成了直接可以形成温敏水凝胶的大分子凝胶因子，构筑了温敏水凝胶体系用于肿瘤的治疗；此外，构筑了基于肿瘤细胞膜的水凝胶制剂用于肿瘤的免疫治疗。此外，我们构筑了金属有机框架材料以及硫化铜、石墨烯等无机纳米载体用于抗肿瘤治疗，均获得了较好的抗肿瘤效果。以上相关研究结果在Adv. Funct. Mater., J. Controlled Release, Nano Letters, Small, Chem. Eng. J., Acta Biomater., ACS Appl. Mater. Interfaces, Nanoscale Horiz., Adv. Healthcare Mater.等杂志上发表论文30篇；其中第一标注15篇，第二标注15篇；授权专利7项，培养研究生18名，博士后1名，参加国内外学术会议6次，培养的研究生张会苑获得山东省优秀博士论文，胡旭、李倩获得山东省优秀硕士论文等。