基于肿瘤微环境响应型可注射水凝胶的化疗-免疫联合治疗共载系统

肿瘤干细胞Wnt/β-catenin信号通路过表达是其自我更新、无限增殖的根源，并促进相关上皮性质的细胞发生间质转化，导致肿瘤发生和侵袭转移。下调Wnt/β-catenin相关基因表达，将有利于逆转肿瘤干细胞的间质性特性，从而有效抑制肿瘤细胞的生长、转移和复发。同时，高表达Wnt/β-catenin的肿瘤往往对PD-1抑制剂治疗无响应，可能与肿瘤干细胞诱发的上皮间质转化相关。本项目针对肿瘤组织高浓度活性氧以及微酸性环境，设计可注射的活性氧敏感和pH敏感的肿瘤微环境响应型可控释药水凝胶-纳米胶束共载系统，装载盐霉素和PD-1抑制剂，以高、低转移能力的乳腺癌细胞系和动物肿瘤模型为研究对象，以盐霉素抑制肿瘤干细胞Wnt信号通路，抑制肿瘤干细胞诱导的上皮间质转化，逆转和增强肿瘤的免疫应答，PD-1抑制剂激活T细胞，通过化疗-免疫联合治疗增强治疗效果。

Over express of Wnt/β-catenin in cancer stem cells (cells) results in the renewal and unlimited proliferation of CSCs, and promotes epithelial-mesenchymal transition (EMT) of related tumor cells, which is considered the reason of rumor growth and neoplasm metastasis. To down regulate the Wnt/β-catenin signal pathway is a promising approach to reverse the stemness of CSCs, and thus depresses tumor growth, metastasis, and recurrence. Meanwhile, tumors with overexpressed Wnt/β-catenin pathway are frequently related with the immunologic escape from the immune checkpoint blockade therapy of PD-1 inhibitor, which might be related with the EMT induced by CACs. Therefore, in this project, tumor microenvironment responsive injectable hydrogel is proposed to co-delivery salinomycin and PD-1 inhibitor for chemo-immune combinational therapy. Salinomycin is loaded in a pH sensitive micelles and then encapsulated in hydrogel with PD-1 inhibitor. It is expected that the salinomycin, which will be released fleetly, could down regulate the expression of Wnt/β-catenin pathway of CSCs, depress the EMT of tumor, enhance the immune response to PD-1 immunogenic therapy, and rise the curative effect of PD-1 inhibitor treatment, reduce the possibility of neoplasm metastasis and tumor recurrence.