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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：
10903125
负责人：
Ashley Carson Brown
金额：
$ 8.26万
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/10903125
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 Emergency Medicine Extracellular Matrix Fibrin Fibrinolytic Agents Fibroblasts Fibrosis Gel Goals Heart Hemorrhage In Vitro Injections Injury Intravenous Ischemia Kinetics Mediating Mediator Mission Modeling Mus Myocardial Infarction N-isopropylacrylamide 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 nanoshell novel particle prevent response risk mitigation 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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neonatal coagulopathies: A review of established and emerging treatments.

新生儿凝血病：现有和新兴治疗方法的回顾。

DOI：
10.1177/15353702211006046
发表时间：
2021
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
0
作者：
Moiseiwitsch,Nina;Brown,AshleyC
通讯作者：
Brown,AshleyC

Fibrin-specific poly(N-isopropylacrylamide) nanogels for targeted delivery of tissue-type plasminogen activator to treat thrombotic complications are well tolerated in vivo.

DOI：
10.1002/btm2.10277
发表时间：
2022-05
期刊：
BIOENGINEERING & TRANSLATIONAL MEDICINE
影响因子：
7.4
作者：
Mihalko, Emily P.;Nellenbach, Kimberly;Krishnakumar, Manasi;Moiseiwitsch, Nina;Sollinger, Jennifer;Cooley, Brian C.;Brown, Ashley C.
通讯作者：
Brown, Ashley C.

Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses

DOI：
10.1002/adtp.202100010
发表时间：
2021-03
期刊：
Advanced Therapeutics
影响因子：
4.6
作者：
Seema Nandi;Emily P. Mihalko;K. Nellenbach;Mario Castaneda;John D Schneible;Mary G Harp;Halston Deal;M. Daniele;S. Menegatti;T. Barker;Ashley C. Brown
通讯作者：
Seema Nandi;Emily P. Mihalko;K. Nellenbach;Mario Castaneda;John D Schneible;Mary G Harp;Halston Deal;M. Daniele;S. Menegatti;T. Barker;Ashley C. Brown

Synthesis of sonicated fibrin nanoparticles that modulate fibrin clot polymerization and enhance angiogenic responses.