自放大肿瘤靶向血管阻断剂纳米药物高分子载体材料研究

传统抗肿瘤纳米药物虽然降低了原有化疗药物的毒副作用，但是其疗效与原药相比没有显著优势。其重要原因之一是纳米药物的瘤内渗透能力低，静脉给药后只聚集在肿瘤血管周围，并不能够进一步渗透到远离肿瘤血管的区域，导致其与肿瘤细胞的接触机会少，不能足量地到达其作用靶点——肿瘤细胞。血管阻断剂纳米药物与靶细胞——肿瘤血管内皮细胞接触无障碍，没有化疗纳米药物所存在的实体肿瘤内渗透问题，但是其肿瘤富集仍然依赖于EPR效应，靶向能力不高。本项目拟以聚乙二醇嵌段聚乳酸和聚谷氨酸接枝聚乙二醇为药物载体基础，以凝血靶向多肽GNQEQVSPLTLLKXC和CREKA为靶头，采用化学键合或者物理包覆担载血管阻断剂康普瑞汀A4或者普那布林，基于血管阻断剂导致的肿瘤内出血-凝血级联反应，可放大肿瘤内部凝血信号，从而招募更多的凝血靶头修饰的纳米药物在肿瘤内富集这一基本原理，设计和制备系列自放大肿瘤靶向血管阻断剂纳米药物。

Although the traditional anti-tumor nano-drug can reduce the side effects of the original chemotherapeutic drug, its efficacy has no significant advantage compared with the original drug. One of the important reasons is that nano-drug has low intratumoral penetration capacity. Nano-drug only aggregates around the tumor blood vessels after intravenous administration, and can not further penetrate into the area far away from tumor blood vessels, resulting in less chance of contacting with tumor cells. Therefore, the nano-drug can not reach its target - tumor cells in sufficient quantity. The nano-drug of vascular disrupting agent has no barrier to contact with tumorous vascular endothelial cells. Although nano-drug of vascular disrupting agent don't have penetration problem as chemotherapy nano-drug, its tumor enrichment still depends on EPR effect and its targeting ability is not high enough. This project will use polyethylene glycol block polylactic acid and polyglutamic acid grafted polyethylene glycol as the drug carrier. Peptides GNQEQVSPLTLLKXC and CREKA will be used as the coagulation targeting ligands. Small molecular vascular disruting agents combretastatin A4 or Plinabulin will be loaded by chemical bonding or physical coating. Because vascular disrupting agents can induce intravascular hemorrhage-coagulation cascade, which amplifying the signal of coagulation inside the tumor and recruiting more coagulation-targeted nano-drugs into the tumor. Based on this basic principle, a series of self-amplifying tumor-targeting delivery systems of vascular disrupting agent are designed and prepared.