基于新型pH响应性纳米递药系统的肿瘤间质重编程治疗胆管细胞癌的研究

Intrahepatic cholangiocarcinoma (ICC) is a biliary malignancy linked to poor prognosis. Currently, lack of effective chemotherapy and targeted therapy is still a dilemma in clinical treatment for ICC. Chemo-resistance induced by carcinoma-associated fibroblasts (CAFs) located in tumor stromal, low drug concentration in tumor tissues caused by tumor-stromal obstruction and low vascularization, which are attributable to attenuate anti-tumor effect of chemotherapy in ICC. In this project, we attempt to explore the synergistic effect and illustrate the potential mechanism of TAZ inhibitor combined with VDR agonist in ICC stromal reprogramming. In addition, this study also tries to solve the problem of low drug concentration in ICC induced by low degree of vascularization by the pH-responsive nano-delivery system. To verify the biosafety and mechanism of nanomedicine in the treatment of cholangiocarcinoma, combined VDR agonist and pH-responsive nanocarrier system was performed in a different animal models including PDX model. Our results will provide a treatment new strategy of nano-delivery system combined with chemotherapy in ICC and provide a theoretical basis for impairing the chemoresistance of the intrahepatic cholangiocarcinoma.

肝内胆管细胞癌（ICC）的恶性程度高，临床预后差，目前缺乏有效的化学和靶向药物。在胆管细胞癌肿瘤间质内，肿瘤成纤维细胞（CAFs）介导的化疗耐药、基质阻隔和血管化程度低导致的肿瘤内药物浓度过低是化疗效果差的重要因素。本项目通过研究维生素D受体（VDR）激动剂在ICC间质重编程中的作用，探索VDR激动剂与TAZ抑制剂联合应用在改善肿瘤微环境中的协同效应，并阐明协同效应的分子机制，针对性解决肿瘤间质内CAFs介导的化疗耐药；通过应用前期构建的新型pH响应性纳米递药系统，促进药物在弱酸性的肿瘤微环境中富集，针对性解决肿瘤内药物浓度过低；通过应用新型pH响应性纳米递药系统联合肿瘤间质重编程，在人源性肿瘤异种移植（PDX）等动物模型中评估纳米药物治疗ICC的作用及生物安全性。本项目的研究成果可以为靶向肿瘤间质克服化疗耐药提供理论依据，为胆管细胞癌的纳米递药系统联合化疗提供新策略。

肝内胆管细胞癌（ICC）的恶性程度高，临床预后差，目前缺乏有效的化学和靶向药物。胆管细胞癌的肿瘤微环境极为复杂。在胆管细胞癌肿瘤间质内，肿瘤成纤维细胞（CAFs）介导的化疗耐药、基质阻隔和血管化程度低导致的肿瘤内药物浓度过低是化疗效果差的重要因素。在本项目中，我们研究了VDR激动剂卡泊三醇对胆管细胞癌的肿瘤间质重编程作用，以及卡泊三醇和吉西他滨在抗胆管癌治疗中的协同作用。本项目还成功构建了两种不同的新型纳米递药系统。基于HPG研发的新型纳米递药系统，可以实现VDR激动剂与吉西他滨的有效联合负载。该纳米药物具有良好的pH响应性，可以在一定程度上可以发挥间质重编程和抗肿瘤作用。基于ZIF-8纳米递药系统，我们构建了一种负载了两种药物并联合了光热治疗的纳米药物，这一纳米药物具有良好的pH响应性、光热效应和生物安全性。这种纳米药物实现了化疗-光热协同治疗，取得了良好的肿瘤治疗效果。除此之外，本项目还研究了胆管细胞癌的肿瘤微环境及分子特征，揭示了APOB、CNRIP1/Parkin/PKM2通路以及基因DNA甲基化在胆管细胞癌发生发展中的作用。本项目的研究成果为克服胆管细胞癌化疗耐药提供了理论依据，为肿瘤的新型纳米递药系统研发提供了新策略。