UC San Diego

Myocardial infarction (MI) affects nearly 800,000 people every year in the United States. As it stands, treating patients during the acute phase of MI is highly limited due to the fragility of the infarcted heart. Thus, minimally invasive intravenous administration of targeted nanoscale therapeutics has the potential to allow for more effective treatment of the heart during this acute phase of MI, a therapeutic window in which more invasive procedures are not feasible. Using an ischemia-reperfusion injury model in rats, we assessed three different nanoscale platforms: polynorbornene nanoparticles, a degradable copolymer nanoparticle, and a polynorbornene protein-like polymer. All these systems leverage the enhanced permeability and retention effect in the infarcted region of the heart and extravasates into the injured myocardium, undergoing a morphological switch from the nano to the micron-scale when cleaved by endogenous MMPs in the infarct. First, we demonstrated the aggregation and localization of matrix metalloproteinase (MMP) responsive peptide-polymer amphiphile polynorbornene nanoparticles carrying a small molecule MMP-inhibitor to the heart following acute myocardial infarction (MI). In addition, we showed that drug incorporation onto the nanoparticle backbone improved significantly improved it’s the maximum concentration at which it could be tolerated compared to free drug treatment in vitro while also maintain the drug’s bioactivity. Next, we assess the degradable nanoparticle for cytocompatibility, infarct-localization, and biodistribution over time. We found that this material successfully degrades over time while exhibiting distinct and beneficial biodistribution compared to previous work. Lastly, we investigated the biodistribution and mechanism of accumulation using a protein-like polymer. We observed strong colocalization of this material with necrotic cardiomyocytes in the infarcted region and favorable biodistribution that preferentially biased accumulation in the kidneys over other satellite organs. All these material approaches are highly versatile and can be easily adapted to carry various therapeutic payloads, making them a potential platform for targeted drug delivery to areas of inflammation.