声筛操控星形复合体靶向转运VEGF-B基因和Batimastat干预支架内再狭窄和血栓形成的研究

介入血运重建对降低急性心血管事件病死和致残率具有不可替代的作用。但规范的药物方案和新型药物洗脱支架（DES）的发展与应用，仍不能很好的解决支架内再狭窄（ISR）和支架内血栓形成（IST）。内皮损伤、胶原暴露可快速诱导基质金属蛋白酶（MMP）-1经蛋白酶活化受体-1途径活化血小板，促进其聚集并始动持续的炎症和后续的ISR和IST病理过程。Batimastat具有广谱的MMP拮抗作用，而血管内皮生长因子（VEGF）-B可高度特异的促内皮新生。本研究针对ISR和IST病理进程设计可时序释放VEGF-B基因和Batimastat的可降解星形复合体；并以先前人工结构声场操控微纳米颗粒的研究为基础，探寻适于血管内微操控的、可嵌入支架的声人工微结构，以获得局域强度高、范围宽的可调控声场，实现在体条件下稳定操控星形可降解复合体靶向于支架部位，并通过动物实验评价整套系统对抑制ISR和IST的价值。

Percutaneous coronary intervention holds indispensable role on management of acute cardiovascular events to reduce the mortality and morbidity. In spite of standard pharmaceutical protocols and development of new-generation drug-eluting stents (DES), in-stent restenosis (ISR) and in-stent thrombus (IST) are still cumbersome. Late-stage “catch-up” phenomenon makes the ISR and IST rates even higher in DES treated population than bare metal stent treated population, leading to worse outcome. Under arterial flow stress, metalloproteinase (MMP)-1 located on the surface of platelets can be activated by exposed collagen debris in the case of endothelium injury after the stent implantation. In turn, MMP-1 stimulates protease-activated receptor (PAR)-1 rapidly and the activation and aggregation of platelets. Thus, the continuous inflammation and cascade of ISR and IST are evoked. It is known that Batimastat is a kind of broad-spectrum MMP inhibitor and vascular endothelial growth factor (VEGF)-B contributes to the proliferation and maintenance of only neo-endothelium under pathological conditions. The first aim of this study is to develop a star-shaped biodegradable complex capable of release VEGF-B gene and Batimastat chronologically. By using of this biodegrable complex, Batimastat can be burst released and the VEGF-B gene and Batimastat can be released in a controlled manner. Previously, we have investigated tunable manipulations of micro/nano particles via the acoustic radiation force induced by the artificial structure modulated acoustic field. In this study, we will try to design artificial periodical microstructures embedded in a stent to obtain an in vivo tunable and highly localized acoustic field within a wide space range, in order to capture the drug-loaded star-shaped biodegradable complex firmly and enhance the targeting of it onto the stent injured lesions. The hypothesis, as well as the acoustic and drug-loading platform will be validated with an atherosclerotic rabbit model.