协同增强化疗疗效和免疫效应的靶向高分子纳米药物的研究

The common polymer nanomedicines often only reduce the number of tumor cells (TC), and the antitumor efficacy is still unsatisfactory due to the limitation of tumor microenvironment. Myeloid-derived suppressor cells (MDSC) are an important class of cells in tumor microenvironment, which can inhibit the T cell-mediated tumor immune through secreting the high levels of reactive oxygen species and immunomodulatory factors. So how to reverse the immune tolerance state of tumor microenvironment becomes a new direction for development of polymer naomedicines. This project will exploit two kinds of reduction-responsive polymer nanomedicines, which target to tumor TC and MDSC, respectively. The synergistic effect of the two types of polymer nanomedicines will be realized. As results, on the one hand, the tumor can be controlled and reduced, and the dead tumor cells can provide more tumor antigen for tumor immune response. On the other hand, the suppression of CD8+ T cells will be eliminated through the reduction of MDSC, and more tumor cells will be destroyed with the change of tumor immune tolerance. The above two approaches complement each other, that is, chemotherapy triggers immunotherapy, and simultaneously immunotherapy promotes the efficacy of chemotherapy. The successful implementation of the project will expand the ideas and approaches for exploitation of targeted antitumor nanomedicines.

因受肿瘤微环境的制约，普通高分子纳米药物往往只是消减了肿瘤细胞数量而达不到理想的抗肿瘤效果。髓系抑制性细胞是肿瘤微环境中的一类重要细胞，可通过表达活性氧和免疫调节因子等抑制T细胞介导的抗肿瘤免疫。因此，扭转肿瘤微环境的免疫抑制状态成为高分子纳米药物开发的新方向。本项目拟开发两类分别靶向于肿瘤微环境中肿瘤细胞和髓系抑制性细胞的多肽修饰的还原响应性高分子纳米药物。通过两类纳米药物的协同效应一方面控制或是缩小肿瘤，同时死亡的肿瘤细胞为肿瘤免疫反应提供更多的肿瘤抗原；另一方面髓系抑制性细胞被清除而消除对CD8+ T细胞的抑制，扭转肿瘤免疫抑制状态，从而进一步杀死肿瘤细胞。上述两种途径相互承接和互补，化疗触发免疫治疗，免疫治疗提高化疗疗效。本项目的实施将拓宽靶向抗肿瘤纳米药物的研发思路和方法。

目前，临床上广泛使用的大部分抗肿瘤药物为小分子化合物，存在水溶性差、选择性不足、生物利用度低、对正常组织毒副作用大且治疗效果差等问题。同时因受肿瘤微环境的制约，普通高分子纳米药物往往只是消减了肿瘤细胞数量而达不到理想的抗肿瘤效果。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微环境响应性的智能高分子纳米药物载体，并通过靶向作用和免疫调节作用增强药物在肿瘤组织的蓄积和提高治疗效果。经过系统的体外和体内实验证实本项目所开发的智能高分子纳米载体可显著降低小分子药物的毒副作用，并提高治疗效果。本项目已完成了预定的研究目标。在本项目的资助下在国际知名学术期刊上发表研究论文20篇、撰写邀请综述3篇、申请中国发明专利4项。