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

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.

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。

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，采用化学键合与物理包覆担载血管阻断剂，基于血管阻断剂导致的肿瘤内出血-凝血级联反应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，取得重要结果与关键数据如下：（1）构建了基于链式反应的自放大肿瘤凝血靶向肽修饰的聚谷氨酸接枝聚乙二醇键合康普瑞汀A4（A15-PLG-CA4），成功引发瘤内出血、靶标扩增、循环靶向的“链式自放大”反应，CA4药物肿瘤递送效率约高于无靶向性纳米药物3倍；（2）构建了基于聚谷氨酸的新型高效“凝血靶向”药物控释系统（Apcitide-PLG-IMDQ-N3），与血管阻断剂纳米药物联用后的治愈率高达60%；（3）构建了基于普纳布林衍生物的新型自激活高分子血管阻断剂纳米药物聚谷氨酸接枝普纳布林氨基衍生物（PLG-AmP），联合乏氧敏感前药替拉扎明治疗组中50%的肿瘤完全消失，且肺转移得到有效解决。以上三个体系充分证实了申请人提出的自放大肿瘤靶向策略的可行性与有效性，为开发基于血管阻断剂的新型主动肿瘤靶向递送系统奠定了基础。共发表国际高水平论文15篇，申请中国发明专利7项，项目申请人作为中青年学术带头人成功申请国家杰出青年基金项目，并获得吉林省科学技术进步一等奖，培养博士毕业生4人，硕士毕业生1人。