影像引导超声定点递送R406调控酪氨酸激酶通路治疗低剪应力介导的动脉粥样硬化研究

Atherosclerosis (AS) is one of the important cause of human death. Inflammation is the main mechanism of AS. Low shear stress plays an extremely important role in inducing vascular wall inflammation and promoting the occurrence and development of AS. And there is still no effective resolution. Studying the molecular mechanism and regulate specific signaling pathway is considered as an effective method for AS prevention and treatment. In previous work, we found that low shear stress could trigger the combination of endothelial cell’s Syk and platelet endothelial cell adhesion factor (PECAM-1) and activated Syk, then affected the expression of downstream inflammatory cytokines and induced AS. On this basis, this project intends to take advantage of targeting magnetic microbubbles which could deliver directionally Syk inhibitor R406 and the guidance of ultrasound imaging and blasting of targeted microbubbles. Targeting magnetic microbubble carrying Syk inhibitor R406 would be designed and produced. In the low shear stress region they could concentrate and adhere on endothelial cells.The visual and directional delivery of R406 into cells could be done by means of cavitation. Combination of Syk and PECAM-1 could be regulated. So as to inhibit the vascular wall inflammatory and achieve the purpose of inhibiting AS process. The study of this project intends to provide a new method of prevention of inflammatory induced by low shear stress and targeted treatment for AS.

动脉粥样硬化（AS）疾病是导致人类死亡的主要原因之一，炎症反应是导致AS发生发展的核心机制。低剪应力是诱发血管壁炎症、促进AS的发生发展的关键诱因，但尚无有效的防治措施。研究其分子机制，干预其特异信号通路，被视作预防和治疗AS的有效途径。前期工作发现：低剪应力可触发内皮细胞表面血小板内皮细胞粘附因子（PECAM-1）和酪氨酸激酶(Syk)结合，进而激活Syk，启动下游炎症因子表达，导致动脉粥样硬化的产生。在此基础上，本项目拟利用靶向磁性微泡定点递送的优势，以及超声影像示踪和靶向微泡爆破的功能，制备载荷Syk抑制剂R406的磁性微泡，靶向黏附富集在低剪应力区的内皮细胞，通过超声的空化作用，可视化胞内递送R406，调控Syk与PECAM-1的结合，抑制血管的炎症反应，从而抑制AS发生发展。本项目的研究将为预防低剪应力诱发的炎症反应及靶向治疗AS提供新的方法和思路。

动脉粥样硬化（Atherosclerosis，AS）是一种慢性炎症性疾病，是许多心血管疾病的基础病理变化。相关研究表明血管壁的低剪切应力（LSS）是引发动脉血管内膜局部炎症的一个重要因素，而酪氨酸激酶（Syk）是血管内皮炎症发生时，细胞内信号转导的一个重要信号分子，其磷酸化影响着NLPR3炎症体的激活，上调或下调血管内皮的炎症因子和趋化因子，影响血管内皮的重建。因此，阻断Syk成为免疫调节防治AS的关键一环。多功能造影剂的出现为超声诊断和治疗开拓广阔的应用前景，实时的影像引导和磁性加抗体的靶向递送是增强药物在大中动脉LSS区递送的重要手段。本研究拟使用动脉银夹，以外科手术的方式构建低剪切应力的模型，采用复乳法加上生物素亲和素桥接法构建磁性靶向载药纳泡，以尾静脉注射的方式使纳泡进入血液循环后，通过超声靶向微泡爆破（UTMD）技术，使酪氨酸激酶抑制剂R406在血管LSS区域释放，治疗动脉粥样硬化。