Enzyme responsive nanoparticle delivery of a small molecule MMP inhibitor following acute myocardial infarction

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Project Summary Myocardial infarction (MI) is a main contributor to cardiovascular disease with an annual incidence of 605,000 new attacks and 200,000 recurrent attacks annually. Many of these patients will go on to develop heart failure and ultimately face premature mortality within five years of diagnosis. Current standard of care includes surgical intervention and prescribed medications that attenuate future damage to the heart and mitigate the likelihood of another adverse cardiac event, but they do not treat the damage that has already been done. Though there have been many pre-clinical studies of various cell and biomaterial therapies designed to treat patients post-MI, in most cases they are administered via intramyocardial injections, a method that is not clinically relevant because the heart is too fragile following MI. Thus, there exists a need to develop a therapeutic that can be administered immediately after MI to prevent the extent of damage to the heart. Targeted drug delivery via nanoparticle carriers has renewed promise for many small molecule drugs that have been previously hampered by high dosages and/or poor solubility. Previously, we have demonstrated the aggregation and localization of peptide-polymer amphiphile nanoparticles in the heart following myocardial infarction (MI). Following IV injection, these nanoparticles extravasated from the leaky vasculature into the infarct where endogenous matrix metalloproteinases (MMPs), proteolytic enzymes that degrade the extracellular matrix, cleaved the MMP-responsive peptide to expose the hydrophobic core and form micron-scale aggregates. Building upon this robust nanoparticle system, here we move from a proof of concept platform to an actual therapeutic by conjugating a small molecule drug to the polymer backbone. In doing this, we will investigate the preserved ability of drug- loaded nanoparticles to localize to the infarcted region of the heart and release a biologically active small molecule MMP-inhibitor. In addition, we are interested in improving the targeting capability of our nanoparticles by incorporating a cardiac homing peptide (CHP) sequence that has demonstrated specific localization to the ischemic region of the myocardium. By increasing localization, we will be able to lower the necessary effective dose and decrease any off-target effects. There is not currently a targeted therapeutic that can be administered during the acute phase of MI to prevent damage. While MMP inhibition with small molecule drugs has been shown to decrease left ventricle dilation and expansion following MI, there remains a need for localized, non-invasive delivery to the infarct to make these drugs clinically translatable. Thus, we hypothesize that our targeting NPs will improve drug delivery to the infarcted region of the heart, resulting in decreased MMP activity in the acute MI-stage and improved cardiac function over time.