Heart failure following myocardial infarction (MI) is a leading cause of death in the US. Despite well-established clinical procedures to restore the blood flow, there lacks early interventions to prevent negative left ventricular (LV) remodeling, which results in LV dilation and decreased heart function. Matrix metalloproteinases (MMPs) are overexpressed in the infarcted heart acutely and result in degradation of the extracellular matrix, which contributes to negative LV remodeling. Herein, we have developed a novel MMP-responsive nanoparticle approach for the targeted delivery of a small molecule MMP inhibitor to attenuate negative LV remodeling. The nanoparticles are prepared from dye labeled, drug conjugated peptide-polymer amphiphiles synthesized via ring-opening metathesis polymerization (ROMP). Upon MMP cleavage on the peptide shell, the nanoparticles undergo a morphological switch due to the change in hydrophilic-to-hydrophobic ratio, giving rise to the microscale aggregates that can be physically trapped in the acute MI for sustained drug release. Following an intravenous injection in a rat MI model, we demonstrated successful nanoparticle accumulation and prolonged retention in the heart. Furthermore, an analog of the platform with fully degradable polyphosphoramidate backbone has been created to aid with the tissue clearance. We believe this new strategy holds the potential to bridge the gaps between the basic and clinical research.

Enzyme-responsive nanoparticles for targeted drug delivery to the heart post myocardial infarction

ACS Spring 2022

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