基于血管靶向栓塞策略的抗肿瘤纳米药物设计和机制研究

Selective thrombotic formation in tumor vessels to induce subsequent tumor necrosis is a promising anti-tumor strategy. Nanoparticles can be engineered to perform multiple functions, which provides significant advantages over simple drug entities. In this study, we designed a biocompatible nanoparticle-delivery system to selectively trigger blood clot formation in tumor vasculature. The nanoparticles would be loaded with coagulant drugs and specially engineered to link tumor homing peptide on their surface. The interaction of the nanoparticles and tumor vasculature would induce thrombotic formation in tumor blood vessels by the synergetic effects of nanoparticle accumulation and drug release from the nanoparticles. Tumor specific thrombosis will occlude tumor vasculature and cut off nutrition and oxygen supplies of tumor, and consequenetly exert anti-tumor effects. The safety and in vivo behavior of nanoparticles will be analyzed by clotting assay, in vivo imaging, H&E staining and immune histological analyses. The anti-tumor effects will be assessed using both tumor xenografts and tumor cells. The mechanism of anti-tumor effects of nanoparticles will be further investigated by cell viability assay. This study will lay the foundation for further developing novel nanotechnology-enabled cancer therapeutic agents via targeting tumor vascular system.

选择性栓塞肿瘤组织血管从而诱发肿瘤组织的缺血性坏死是一种很有前景的抗肿瘤策略。本研究将采用纳米技术，结合促凝药物/试剂的生物学特性，设计并构建生物相容性、可靶向作用于肿瘤组织血管的纳米促凝药物新剂型，实现纳米颗粒富集导致物理性栓塞和促凝药物释放诱发生物性栓塞的协同效应，从而阻断肿瘤血供，引发肿瘤缺血性坏死，发挥抗肿瘤作用。本研究将通过凝血功能测定、小动物活体成像、免疫组化等技术手段评价纳米促凝药物的生物安全性并研究其体内代谢行为；在荷瘤小鼠模型上评价纳米药物的抗肿瘤效果，并通过细胞功能分析揭示其在肿瘤血管中促凝的作用机制和细胞毒性。本研究的开展将为开辟肿瘤血管靶向、纳米材料、促凝药物三者有机结合的血管靶向治疗新途径奠定一定的基础，有望为肿瘤血管靶向治疗提供一种高效的药物新剂型。

阻断肿瘤血供治疗法是通过栓塞已存在的肿瘤血管，使肿瘤细胞因缺乏营养和氧气饥饿而死，该疗法针对的靶点是血液成分，见效快、治疗周期短，不易产生耐药性，呈现出较好的临床应用前景。然而，迄今为止寻找安全有效的肿瘤血管栓塞法仍然是该研究领域的一个“瓶颈”。.凝血酶是凝血系统的一种关键酶。它既可以诱导纤维蛋白的产生，也可以激活血小板，最终导致血栓的形成。作为一种高效的促凝剂，如果凝血酶被靶向递送到肿瘤血管，无疑可高效阻断肿瘤血供，达到治疗肿瘤的目的。然而，凝血酶自身的高凝活性使其不适于静脉注射，且它在血液中的半衰期较短。在本项目中我们借助纳米技术首次将凝血酶引入到肿瘤治疗中。首先设计并构建了一种装载有凝血酶的可主动靶向肿瘤血管内皮的聚合物纳米颗粒，实现靶向输运和药物缓释，有效诱导了肿瘤血管栓塞，抑制了肿瘤生长；在此工作基础上我们进一步构建了集靶向性、环境响应释药于一体的智能DNA自组装纳米颗粒，实现了凝血酶对肿瘤血管的高效输运，并取得良好的治疗效果，有望为肿瘤血管栓塞法提供一种高效的药物新剂型。此外，我们还对细胞膜泡纳米结构进行靶向修饰改造，为寻找一种天然的凝血酶输运载体奠定基础。