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

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $38,917

## Abstract

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.

## Key facts

- **NIH application ID:** 10456002
- **Project number:** 5F31HL152610-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Holly Sullivan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,917
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456002

## Citation

> US National Institutes of Health, RePORTER application 10456002, Enzyme responsive nanoparticle delivery of a small molecule MMP inhibitor following acute myocardial infarction (5F31HL152610-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10456002. Licensed CC0.

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