共输送化疗药物/HIF抑制剂的肿瘤微环境响应型纳米凝胶载药系统抗肿瘤作用及机制研究

Considering that hypoxia-inducible factors (HIF) are involved in the CSC enrichment and immune escape induced by hypoxia and anticancer drugs, which enhanced drug resistance in cancer, the development of nano drug delivery systems (NDDS) which can simultaneously co-deliver chemotherapeutics and HIF inhibitors to normal cancer cells and cancer stem cells (CSCs) might improve cancer therapy efficacy. To overcome several barriers during the drug delivery, this project will develop CD133 (a surface marker of liver CSCs) aptamer A15-conjugated tumor microenvironment-responsive nanogels with simultaneous hydrophilic/hydrophobic reversal and surface charge reversal regulated by pH and redox responsiveness, to co-deliver chemotherapeutics and HIF inhibitors. The biofates of the NDDS, including long circulation, tumor retention and penetration, cellular uptake, lysosomal escape and intracellular drug release will be systematically investigated under normoxia and hypoxia. The effects of the NDDS on the killing nomal liver cancer cells and liver CSCs, inhibition of anticancer drugs-induced liver CSCs enrichment and regulation of tumor immune microenvironment will be elucidated. This project will provide an insight into developing effective tumor-targeted NDDS and offer a novel strategy for targeted therapy for CSCs.

基于HIF在缺氧和化疗药物诱导的肿瘤干细胞富集、促进肿瘤免疫逃逸、增强肿瘤耐药性方面的重要作用，发展共输送化疗药物与HIF抑制剂的纳米载药系统同时靶向普通肿瘤细胞和肿瘤干细胞，有望提高肿瘤治疗效果。为克服药物输送过程中的多重屏障，本项目针对肿瘤组织和肿瘤细胞内微环境，构建具有pH调控的可同时亲疏水性反转和电荷反转、氧化还原响应性的纳米凝胶，并偶联肝癌干细胞表面标志物CD133的核酸适配体A15，用于化疗药物和HIF抑制剂的靶向共输送，系统研究在常氧和缺氧条件下此载药纳米凝胶的长循环、肿瘤组织滞留和渗透、肿瘤细胞摄取、溶酶体逃逸和胞内响应性释药等体内过程；细胞及动物层面评价此载药纳米凝胶对普通肝癌细胞和肝癌干细胞的杀伤效果及抑制化疗药物诱导的肝癌干细胞富集，探讨其对肿瘤免疫微环境的调控。本项目的实施将为设计更为有效的肿瘤靶向纳米载药系统提供理论基础，并为肿瘤干细胞的靶向治疗提供新途径。

如何实现体内长循环、肿瘤组织高度富集及深部穿透、被肿瘤细胞和肿瘤干细胞有效摄取及可控释药是抗肿瘤纳米药物面临的主要挑战。本项目构建肿瘤酸性微环境调控的亲疏水性/电荷反转及氧化还原响应型温敏纳米凝胶载药系统，其在血液循环过程中呈亲水性，有利于长循环；到达肿瘤组织后，在肿瘤微酸性环境下迅速反转成疏水性，有利于其在肿瘤组织高度富集、肿瘤深部穿透、被肿瘤细胞和肿瘤干细胞有效摄取；进入肿瘤细胞后在溶酶体强酸性环境中电荷反转成正电荷，有利于其溶酶体逃逸，并在细胞质高GSH条件下响应性释放抗肿瘤药物，发挥良好的抗肿瘤及杀伤肿瘤干细胞的作用。在此基础上，开发了系列基于智能响应型温敏纳米凝胶和聚合物的纳米药物，如共输送化疗药物和光敏剂的纳米凝胶载药系统、基于金纳米笼的智能响应光热-化疗协同治疗平台等用于改善肿瘤治疗。本项目对提高抗肿瘤药物治疗效果提供理论依据。