Chen Binfan, Gao Ang, Tu Bin, Wang Yonghui, Yu Xiaolu, Wang Yingshu, Xiu Yanfeng, Wang Bing, Wan Yakun, Huang Yongzhuo
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Biomaterials. 2020 Oct;255:120187. doi: 10.1016/j.biomaterials.2020.120187. Epub 2020 Jun 12.
Tumor microenvironment (TME) closely affects cancer progression by promoting cancer cell survival and proliferation, drug resistance, metastasis, and immunosuppression as well. Remodeling TME is a promising therapeutic strategy for anticancer. mTOR signaling is an essential regulator for cellular metabolism and tumor-associated macrophages (TAMs) repolarization. There is an integrated crosstalk among mTOR/metabolism/immunity. Angiogenesis can also regulate metabolism and immunity. Based on these, a potential therapeutic avenue was developed by targeting mTOR and angiogenesis to remodel tumor immune microenvironment (TIME). A dual-targeting delivery liposomal system was designed with dual-modification of PD-L1 nanobody and mannose ligands for co-delivering an mTOR inhibitor (rapamycin) and an anti-angiogenic drug (regorafenib). The liposomes were able to target both TAMs and cancer cells that overexpressed PD-L1 and mannose receptors. The liposomes efficiently reduced glycolysis, repolarized TAMs, inhibited angiogenesis, reprogrammed immune cells, and consequently arrested tumor growth.
肿瘤微环境（TME）通过促进癌细胞存活、增殖、耐药、转移以及免疫抑制等，密切影响癌症进展。重塑肿瘤微环境是一种很有前景的抗癌治疗策略。mTOR信号传导是细胞代谢和肿瘤相关巨噬细胞（TAM）极化的重要调节因子。mTOR/代谢/免疫之间存在综合的相互作用。血管生成也可调节代谢和免疫。基于此，通过靶向mTOR和血管生成来重塑肿瘤免疫微环境（TIME），开发了一条潜在的治疗途径。设计了一种双靶向递送脂质体系统，对PD-L1纳米抗体和甘露糖配体进行双重修饰，用于共同递送mTOR抑制剂（雷帕霉素）和抗血管生成药物（瑞戈非尼）。这些脂质体能够靶向过表达PD-L1和甘露糖受体的TAM和癌细胞。脂质体有效降低糖酵解、使TAM极化、抑制血管生成、重编程免疫细胞，从而阻止肿瘤生长。
