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

使用双重递送微凝胶治疗剂靶向治疗血栓闭塞

基本信息

批准号：
10223925
负责人：
Ashley Carson Brown
金额：
$ 36.8万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223925
关键词：
Acute Address Affinity Alteplase Antibodies Anticoagulant therapy Anticoagulants Atherosclerosis Binding Blood Vessels Blood flow Cardiac Output Catheters Cells Cessation of life Chronic Cicatrix Clinical Coagulation Process Coupled Cytolysis Data Deep Vein Thrombosis Deposition Drug Controls Drug Delivery Systems Electrolytes Emergency Medicine Extracellular Matrix Fibrin Fibrinolytic Agents Fibroblasts Fibrosis Goals Heart Hemorrhage In Vitro Injections Injury Intravenous Ischemia Kinetics Mediating Mediator of activation protein Mission Modeling Mus Myocardial Infarction NanoGel Outcome Peptides Play Postphlebitic Syndrome Procedures Production Public Health Pulmonary Embolism Rattus Reperfusion Injury Reperfusion Therapy Resolution Rho-associated kinase Risk Rodent Rodent Model Role Rural Signal Transduction Site System Therapeutic Therapeutic Embolization Thrombolytic Therapy Thrombosis Thrombus Tissues Toxic effect Treatment Efficacy United States National Institutes of Health Venous Thrombosis Work body system coronary fibrosis crosslink design drug release profile ferric chloride improved in vivo in vivo Model intravenous administration ischemic injury kinase inhibitor novel particle poly-N-isopropylacrylamide prevent response small molecule targeted delivery targeted treatment thrombotic treatment strategy

项目摘要

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.

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。