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

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.

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。

介入血运重建对降低急性心血管事件病死率和致残率具有不可替代的作用。为了应对支架内血栓形成常需口服多种抗栓药物，造成出血风险增加。本项目提出并验证了人工结构声场操控微纳颗粒的理论，证实共振激发的非泄露A0模式Lamb波在垂直板面方向产生的高度局域化的声场和平行于板面的周期声场，显著增强了颗粒受到的声辐射力和声流拽力；同时，该共振诱发了一种超快速类Rayleigh流，其与经典Rayleigh流的流场结构相似，但最大速度却高4个数量级，且具有更小的涡旋尺寸。根据理论研究，课题组搭建了在体声学操控微纳颗粒的系统平台。另一方面，课题组研制了兼具血管内声人工微结构和机械性支撑性能的可降解“声筛支架”，首次在体内获得了局域强度高、范围宽的可调控声场，建立了在体声学操控微泡的方法学。第三方面，本项目构建了可对抗高剪切力流体环境的多功能微泡-中性粒细胞靶向转运载体，具有大载荷容积，在实现超声示踪的同时，可充分利用所建立的操控方法，在体实现该转运载体稳定靶向于支架部位，不仅可阻抑支架内血栓形成并对早期形成的支架内血栓具有溶栓效果，还可以实现高效转运药物至动脉粥样硬化病变内。此外，本项目的研究成果在快速混合、细胞/颗粒筛选、药物输运、基因转染、神经刺激、细胞操控等生物医学应用方面具有广泛的应用前景。