免疫细胞功能仿生的颗粒酶B与穿孔素联合投递纳米微囊设计及肿瘤抑制研究

The potential utility of cells based immunotherapy for hematologic malignancies treatment, such as leukemia and lymphoma has made a breakthrough and played an increasingly important role in clinical studies. Nevertheless, the effect of immunotherapy in solid tumor still need to be improved due to the limitations of tumor microenvironment and tumor cell characteristics. To solve this problem, based on the mechanism that be involved in immune-targeted cell death , in recent study, we prepared a new Granzyme B tumor targeting delivery system based on single protein nanocapsule technology we previously reported and this systerm significantly inhibited the growth of tumour in nude mice. In order to further improve the transmembrane efficiency of granzyme B and the ability of inducing cell apoptosis, in this subject, we propose a new Granzyme B and perforin tumor targeting co-delivery system that fully simulated NK/CTL cell mediate cancer immunotherapy process. In addition, the mechanism of perforin-mediated granzyme B transmembrane was discussed, and the in vitro and in vivo antitumor effects of perforin and granzyme B were defined. Also the Granzyme B / perforin co-delivery system in tumor distribution and effective inhibition of solid tumors were established. Finally achieving the biomimetics function of immune cells and providing new ideas for the tumor immune therapy.

细胞免疫疗法在白血病和淋巴瘤等血液系统肿瘤治疗中取得了突破性进展并在临床中发挥越来越重要的作用，然而由于肿瘤微环境和肿瘤细胞特点的限制，在实体瘤中免疫细胞疗法效果仍待进一步提高。为了解决此问题，本课题组基于免疫细胞杀伤靶细胞的机理，前期以单蛋白纳米微囊技术为基础，制备了靶向肿瘤组织并响应性释放颗粒酶B的纳米投递系统，显著抑制了裸鼠体内肿瘤的增长。为了进一步提高颗粒酶B的跨膜效率和诱导肿瘤细胞凋亡的能力，本课题拟设计并制备颗粒酶B和穿孔素联合纳米投递系统，并模拟CTL/NK细胞杀伤肿瘤过程，同时探讨穿孔素介导颗粒酶B的跨膜机制，明确穿孔素与颗粒酶B联合投递的体内外抑瘤效果，从而确定颗粒酶B/穿孔素投递系统在肿瘤内部分布及对实体瘤的抑制功能，实现免疫细胞的功能仿生，为肿瘤的免疫治疗和新药的研制提供新的思路。

细胞免疫疗法在白血病和淋巴瘤等血液系统肿瘤治疗中取得了突破性进展并在临床中发挥越来越重要的作用，然而由于肿瘤微环境和肿瘤细胞特点的限制，在实体瘤中免疫细胞疗法效果仍待进一步提高。为了解决此问题，本课题组基于免疫细胞杀伤靶细胞的机理，以单蛋白纳米微囊技术为基础，制备了靶向肿瘤组织并响应性释放颗粒酶B的纳米投递系统，显著抑制了裸鼠体内肿瘤的增长。为了进一步提高颗粒酶B的跨膜效率和诱导肿瘤细胞凋亡的能力，本课题拟设计并制备颗粒酶B和穿孔素联合纳米投递系统，并模拟CTL/NK细胞杀伤肿瘤过程，同时探讨穿孔素介导颗粒酶B的跨膜机制，明确穿孔素与颗粒酶B联合投递的体内外抑瘤效果，从而确定颗粒酶B/穿孔素投递系统在肿瘤内部分布及对实体瘤的抑制功能，实现免疫细胞的功能仿生，为肿瘤的免疫治疗和新药的研制提供新的思路。