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

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.