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：
10457953
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/10457953
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.

项目摘要动脉和静脉血栓形成会在多种组织中引起缺血性损伤。闭塞可能会缓慢出现从动脉粥样硬化疾病的进展或由于血栓栓塞引起的急性。严重的临床血栓性闭塞的表现包括心肌梗塞（MI），深静脉血栓形成（DVT）和肺栓塞（PE）。快速恢复血流对于预防血栓形成后死亡至关重要然而，闭塞的再灌注会导致疤痕组织，从而限制随后的组织功能。例子在DVT之后，包括MI和栓性后综合征后，包括心脏纤维化。不幸的是，无效已经建立了防止血栓解决后纤维化的策略。该提议的目的是开发一种新型的有针对性的双重治疗系统，用于治疗血栓性遮挡，以解决关键需要重新填充阻塞的血管并防止随后的纤维化。我们将通过结合来实现这一目标纤维蛋白靶向粒子平台，具有临时递送的纤维蛋白水解药物，该平台将恢复血液流向缺血组织，然后流向小分子Rho相关激酶（岩石）抑制剂，这将阻止涉及纤维化发作和进展的钥匙细胞反应。这项工作很重要因为这是解决快速再生组织和治疗的关键需求的第一个治疗策略血小板阻塞后随后的纤维化。