靶向栓塞治疗肝癌的生物纳米栓塞剂抗肿瘤活性与体内效应研究

Hepatocellular carcinoma(HCC), which is a common malignant tumor in China. However, curative treatment for early stage HCC such as resection is carried out in only a small portion of the patients. Transcatheter arterial chemoembolization has been performed worldwide for the patients with unresectable hepatocellular carcinoma. However, some drawbacks such as partial embolization and off-target embolization still exist with current embolic agents. Therefore, it is urgent to develop novel embolic agents dealing with these problems. Intelligent nanodrug systems have great potential as specific targeting and environment responsive vehicles to enable the delivery of various potent molecules, which otherwise never could be used as therapeutics due to numerous limitations. Our novel embolic agent, based on natural coagulation agent thrombin and its derivatives, could realize targeted delivery of the thrombin molecules via our validated tumor vasculature targeting strategy. Such specific delivery of thrombin molecules could cause on-site tumor infarction specifically. Therefore, our novel nano-embolic agents could enhance therapeutic effect and reduce the side effects of current agents, representing a promising strategy for precise drug design for HCC therapeutics. It has been well planed to design and synthesis a series of thrombin-loaded nanoparticles. After careful characterization and functional validation in vitro and in vivo, the optimal nanomedicines will be chose to evaluate their functionality in rabbit VX2 carcinoma models. Systemic pharmacokinetics and toxicology studies will be carried out in the purpose of supporting clinical transformation in the near future. In conclusion, this program is built up with sufficient previous foundations and well designed research plan. These nanomaterials enabled specific tumor delivery of thrombin holds a great promise for future application.

肝癌是我国常见的恶性肿瘤，多数患者在初诊时失去手术根治的机会，对于中晚期病人目前没有有效的治疗手段。目前，肝动脉化疗栓塞（transcatheter arterial chemoembolization, TACE）已成为不可切除肝癌的首选治疗方式。然而现有栓塞剂存在栓塞不彻底、无靶向性等缺点。因此，急需开发新型栓塞剂。新型凝血酶纳米栓塞剂可实现凝血酶的靶向释放，从而快速阻断血流实现永久栓塞，是改善肝癌栓塞治疗疗效、降低副作用的潜在药物新剂型。本课题设计构建不同靶向原理的凝血酶纳米栓塞剂，开展纳米材料表征检测以及体内功能研究；进一步在兔VX2肝癌模型中对比验证其与现有栓塞剂的治疗效果；系统开展凝血酶纳米栓塞剂与肝脏的相互作用研究，以及对机体代谢的潜在影响，利用小鼠和小型猪（Bama）模型系统对其安全性进行评价，为进行临床转化打下坚实基础。

为解决临床现有肿瘤血管栓塞剂靶向性差、栓塞不彻底、操作复杂、治疗费用高等问题，切实提高肝癌患者的生存期与生存质量，项目组构建了多种新型生物纳米栓塞剂，精准、高效的诱发肿瘤血管内血栓形成，快速、长久阻断肝癌血供。此外，为了进一步提高肝癌血管栓塞治疗的疗效，我们将肝癌的血管栓塞治疗与化疗、免疫治疗等疗法高效的联合起来，利用纳米平台的集成优势，在栓塞肿瘤血管的同时释放化疗药物与免疫检查点抑制剂。相比临床现有肿瘤血管栓塞剂，新型肿瘤血管栓塞药物具有给药方便、疗效更好、安全性更高等独特优势。.实验结果表明，项目组发展的多功能肿瘤血管栓塞剂可以显著提高肿瘤的抑制率并有效延长小鼠的生存期。在本项目的资助下，项目组发展5种新型生物纳米栓塞剂，发表SCI论文33篇，包括Nature Biotechnology, Nature Biomedical Engineering, Science Translational Medicine等多篇国际权威期刊。申请中国发明专利8项，转化专利1项，并成功孵化“北京君全智药科技有限公司”与“北京易维智药科技有限公司”两家高科技生物医药公司。本项目从临床肝癌治疗的痛点问题出发，设计多种具有临床转化潜力的肿瘤血管栓塞剂，为中晚期肝癌的治疗提供了新思路，极大改善了现有肝癌治疗策略的疗效并有望提高肝癌患者的生存期与生存质量，降低临床上肿瘤血管栓塞治疗的费用，减轻了我国肿瘤治疗的压力和负担，具有强大的临床意义和社会价值。

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