Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic.
Emily MihalkoKe HuangErin SproulKe ChengAshley C BrownPublished in: ACS nano (2018)
Myocardial infarction (MI), commonly known as a heart attack, affects millions of people worldwide and results in significant death and disabilities. A major cause of MI is fibrin-rich thrombus formation that occludes the coronary arteries, blocking blood flow to the heart and causing fibrin deposition. In treating MI, re-establishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly( N-isopropylacrylamide) nanogels (FSNs) comprised of a core-shell colloidal hydrogel architecture are utilized in this study to design a dual-delivery system that simultaneously addresses the need to (1) re-establish blood flow and (2) inhibit cardiac fibrosis following I/R injury. These therapeutic needs are met by controlling the release of a fibrinolytic protein, tissue plasminogen activator (tPA), and a small molecule cell contractility inhibitor (Y-27632). In vitro, tPA and Y-27632-loaded FSNs rapidly degrade fibrin and decrease cardiac cell stress fiber formation and connective tissue growth factor expression, which are both upregulated in cardiac fibrosis. In vivo, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction 2 and 4 weeks post-I/R as well as significantly decreased infarct size, α-smooth muscle actin expression, and connective tissue growth factor expression 4 weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI.
Keyphrases
- blood flow
- left ventricular
- growth factor
- heart failure
- aortic stenosis
- smooth muscle
- poor prognosis
- ejection fraction
- cancer therapy
- drug delivery
- small molecule
- acute myocardial infarction
- hypertrophic cardiomyopathy
- cardiac resynchronization therapy
- platelet rich plasma
- binding protein
- mitral valve
- left atrial
- single cell
- atrial fibrillation
- coronary artery disease
- coronary artery
- protein protein
- risk factors
- stem cells
- cell therapy
- transcatheter aortic valve replacement
- long non coding rna
- wound healing
- systemic sclerosis
- gestational age
- subarachnoid hemorrhage
- combination therapy
- hyaluronic acid
- artificial intelligence
- data analysis
- preterm birth