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

项目总结 动脉和静脉血栓可导致多种组织的缺血性损伤。闭塞可能会慢慢出现 由于动脉粥样硬化性疾病的进展或由于血栓栓塞术引起的急性死亡。严重临床 血栓闭塞的表现包括心肌梗死(MI)、深静脉血栓形成(DVT)和 肺栓塞(PE)。迅速恢复血流是预防血栓形成后死亡的关键 然而，闭塞再灌注可能会导致疤痕组织，从而限制后续的组织功能。示例 包括心肌梗死后的心脏纤维化和深静脉血栓形成后的血栓后综合征。不幸的是，没有有效的 已经制定了预防血栓消退后纤维化的策略。这项提议的目的是 是开发一种新的靶向双重治疗系统来治疗血栓闭塞，以解决 需要对阻塞的血管进行再灌流，防止随后的纤维化。我们将通过以下方式实现这一点： 一种纤维蛋白靶向微粒平台，具有时间控制的纤溶药物输送，可以恢复血液 流向缺血组织，随后输送小分子Rho相关激酶(ROCK)抑制剂， 这将阻断参与纤维化发生和发展的关键细胞反应。这项工作意义重大 因为它是解决关键需求的第一种治疗策略，即快速组织再灌流和治疗 血栓闭塞后的后续纤维化。

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.