“可视化”温敏水凝胶缓释化疗药物/基因用于耐药性肝癌介入栓塞治疗的研究

Unsatisfied designs of current embolic agents and drug resistance caused by long term embolization chemotherapy are important reasons leading to the failure of interventional therapy in hepatocellular carcinoma. Rational designs of long term effective and controllable hepatic artery embolization therapeutics with drug resistance overcoming ability, as well as improving patient survival rate are crucial issues in treating hepatocellular carcinoma. In preliminary studies, we found that multi-block polymers PEG/PPG/PHB showed unique advantages in new pharmaceutical designs, due to their low critical gelation concentration, thermosensitive and injectable ability, good biocompatibility, biodegradability, high transparence in hydrogel states, as well as long term and effective drug sustained release ability. In this project, we propose to use PEG/PPG/PPHB combined with an aggregation induced emission (AIE) molecule and cationic gene vector PEI, to construct a "visual" multifunctional embolization therapeutic agent; to real-time monitor solid gelation process of thermosensitive polymer aqueous solution in blood vessels of hepatocellular carcinoma at body temperature as well as their stability, which can be beneficial for embolization mechanism investigation and provide guidance for second embolization therapy; by constructing rabbit VX2/Bcl-2 drug resistant liver tumor model, to take the advantages of hydrogel’s drug/gene co-delivery ability for long term as well as locally sustained release of chemotherapeutic drugs / anti-apoptotic and drug resistant Bcl-2 protein conversion Nur77 gene; in order to provide a novel approach and mechanism for interventional precise treatments of drug resistant hepatocellular carcinoma, from the pharmaceutical point of view.

目前栓塞剂的不良设计及长时间栓塞化疗所引起的肿瘤耐药性是导致肝癌介入治疗失败的重要原因，如何设计长效可控的肝动脉血管栓塞治疗剂并攻克耐药性、提高患者存活率是目前肝癌治疗中迫切需要解决的课题。前期研究中，我们发现多嵌段高分子聚合物PEG/PPG/PHB具有低临界凝胶浓度、温敏可注射、良好生物相容性、可降解、高凝胶透明度及长效药物缓释能力，在药物新剂型设计上拥有独特的优势。本项目中，我们将利用PEG/PPG/PHB结合聚集诱导发光AIE分子以及阳离子基因载体PEI，构建“可视化”多功能栓塞治疗剂；实时监控肝癌血管中的温敏水溶液在体温下固化凝胶过程及其稳定性，为栓塞机制探索及二次栓塞提供指导；构建兔VX2/Bcl-2耐药肝癌模型，利用该水凝胶的药物/基因共载能力，长效局部缓释化疗药物/可逆转肿瘤耐药性Bcl-2蛋白抗凋亡功能的Nur77基因，从药剂角度为耐药性肝癌介入精准治疗提供新思路及新机制。

目前栓塞剂的不良设计及长时间栓塞化疗所引起的肿瘤耐药性是导致肝癌介入治疗失败的重要原因，如何设计长效可控的肝动脉血管栓塞治疗剂并攻克耐药性、提高患者存活率是目前肝癌治疗中迫切需要解决的课题。我们的前期研究表明高效低毒的多功能载体设计是实现肿瘤协同增效治疗的关键，本课题进一步设计具有良好生物相容性、生物可降解的多嵌段温敏两亲性聚合物，结合聚集诱导发光AIE分子以及阳离子基因载体，构建“可视化”多功能栓塞治疗剂；实时监控肝癌血管中的温敏水溶液在体温下固化凝胶过程及其稳定性，为栓塞机制探索及二次栓塞提供指导；简便高效地将凝血酶和化疗药物阿霉素（DOX）封装至高分子聚合物水凝胶中，并提出将具有具有良好的生物相容性的温度响应智能水凝胶用于肿瘤血管栓塞治疗，实现肿瘤供血血管的有效栓塞，在起到阻断肿瘤细胞营养供给的同时，水凝胶的降解伴随着DOX的释放，协同实现化疗药物浓度的局部提高并延长药物在用药部位的滞留时间，显著地抑制住了肿瘤的生长；构建Bcl-2耐药肝癌模型，利用水凝胶的药物/基因共载能力，长效局部缓释化疗药物/可逆转肿瘤耐药性Bcl-2蛋白抗凋亡功能的基因，从药物新制剂角度为耐药性肝癌介入精准治疗提供新思路。有关成果整理形成了30篇SCI文章（均有标注本基金81773661资助；包括Small Methods, 2021 (IF: 14.188); Bioactive Materials, 2022 (IF: 14.593); Small, 2018 (IF: 13.281); Chemical Engineering Journal, 2021, 2篇 (IF: 13.273); Advanced Healthcare Materials, 2018 & 2019, 3篇 (IF: 9.933)等）。综上，我们已完成了项目所规定的任务和预期目标，并有新的发现和进展。