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

Author:

Eding Joep E. C.1,Vigil‐Garcia Marta1,Vink Marit1,Demkes Charlotte J.2,Versteeg Danielle2,Kooijman Lieneke1,Bakker Maarten H.3,Schotman Maaike J. G.3,Dankers Patricia Y. W.3ORCID,van Rooij Eva2

Affiliation:

1. Hubrecht Institute KNAW University Medical Center Utrecht Utrecht 3584 CT The Netherlands

2. Hubrecht Institute KNAW Department of Cardiology University Medical Center Utrecht Utrecht 3584 CT The Netherlands

3. Institute for Complex Molecular Systems Department of Biomedical Engineering Laboratory of Chemical Biology Eindhoven University of Technology Eindhoven 5600 MB The Netherlands

Abstract

AbstractMicroRNAs (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.

Funder

FP7 Ideas: European Research Council

Ministerie van Onderwijs, Cultuur en Wetenschap

Hartstichting

Publisher

Wiley

Subject

Pharmacology (medical),Biochemistry (medical),Genetics (clinical),Pharmaceutical Science,Pharmacology,Medicine (miscellaneous)

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