Targeted treatment of thrombotic occlusions using a dual-delivery microgel therapeutic

项目摘要 动脉和静脉血栓形成可导致多种组织的缺血性损伤。闭塞可以慢慢出现 动脉粥样硬化疾病的进展或急性血栓栓塞。严重临床 血栓性闭塞的表现包括心肌梗死（MI）、深静脉血栓形成（DVT）和血栓性心脏病（AMI）。 肺栓塞（PE）。快速恢复血流对于预防血栓性疾病后死亡至关重要 然而，在闭塞的情况下，再灌注可导致瘢痕组织，这限制了随后的组织功能。示例 包括MI后心脏纤维化和DVT后血栓形成后综合征。不幸的是，没有有效的 已经建立了预防血栓消退后纤维化的策略。本提案的目的 目的是开发一种新的靶向双重治疗系统，用于治疗血栓性闭塞， 对阻塞的血管进行再灌注并防止随后的纤维化是至关重要的。我们将通过结合 一种纤维蛋白靶向颗粒平台，其具有纤维蛋白溶解药物的时间受控递送，其将恢复血液 流向缺血组织，随后递送小分子Rho相关激酶（ROCK）抑制剂， 其将阻断与纤维化的发生和发展有关的关键细胞反应。这项工作意义重大 因为它是第一个治疗策略，以解决快速再灌注组织和治疗的关键需求 血栓闭塞后的纤维化。

PROJECT SUMMARY Arterial and venous thrombosis can cause ischemic injuries in a multitude of tissues. Occlusions can arise slowly from the progression of atherosclerotic disease or acutely due to thrombo-embolization. Serious clinical manifestations of thrombotic occlusions include myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE). Quickly restoring blood flow is critical for preventing death following thrombotic occlusions, however, reperfusion can result in scar tissue that limits subsequent tissue function. Examples include cardiac fibrosis following MI and post-thrombotic syndrome following DVT. Unfortunately, no effective strategies have been established to prevent fibrosis following thrombus resolution. The objective of this proposal is to develop a novel targeted dual therapeutic system for treatment of thrombotic occlusions that addresses the critical needs to reperfuse the blocked vessel and prevent subsequent fibrosis. We will achieve this by combining a fibrin-targeting particle platform with temporally controlled delivery of a fibrinolytic drug, which will restore blood flow to the ischemic tissue, followed by delivery of a small molecule Rho-associated kinase (ROCK) inhibitor, which will block key cellular responses involved in the onset and progression of fibrosis. This work is significant because it is the first treatment strategy to address the critical needs to quickly reperfuse tissue and treat subsequent fibrosis following thrombotic occlusions.