Hydrogel-Based Delivery of antimiR-195 Improves Cardiac Efficacy after Ischemic Injury

Abstract

MicroRNAs (miRs) are potent regulators of biology and disease. The miR-15 family is shown to regulate cardiomyocyte proliferation and antimiR-based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. Injectable hydrogels are proposed to serve as sustained-release drug delivery depots and can potentially be used to improve cardiac efficacy of antimiR therapeutics. Here, the effect of a hydrogel-formulated antimiR-195 after myocardial infarction in mice is studied. For this, an injectable, pH-switchable supramolecular hydrogel based on poly(ethylene glycol) (PEG) functionalized with hydrogen bonding ureido-pyrimidinone (UPy) units is used. Intracardiac injections under baseline conditions of this UPy–PEG hydrogelator induce a transient inflammatory response that is no longer present 7 days postinjection. In vitro experiments show that antimiR-195 is released from the gel, and induces microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR-195 in UPy–PEG enhances cardiac target derepression compared to phosphate-buffered-saline-dissolved antimiR-195, despite a low cardiac retention. After ischemic injury, this translates into a greater therapeutic effect by increasing both target derepression and cardiomyocyte proliferation. Intramyocardial injection of UPy–PEG-formulated antimiR-195 is sufficient to improve cardiac efficacy of antimiR-195.