Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart

Abstract

Injectable hydrogels have significant therapeutic potential for treatment of myocardial infarction (MI) through tissue bulking and local drug delivery, including the delivery of small interfering RNAs (siRNAs). As siRNA targets are identified as potential treatments for MI, hydrogels may bolster efficacy through local and sustained release. Here, we designed an injectable hydrogel to respond to local upregulation in proteolytic activity after MI to erode and release siRNA against MMP2 (siMMP2), a target implicated in deleterious remodeling. Specifically, hyaluronic acid (HA) was modified with hydrazides or aldehydes and mixed to form shear-thinning and self-healing hydrogels through dynamic hydrazone bonds and with peptide crosslinkers that degrade in response to protease activity. HA was further modified with β-cyclodextrin to sequester cholesterol-modified siRNA, limiting passive diffusion. Hydrogels eroded in response to proteases and released active siRNA that knocked down MMP2 in primary cardiac fibroblasts. In a rat model of MI, hydrogels delivering siMMP2 attenuated hydrogel erosion by ~46% at 4 weeks when compared to hydrogels delivering control siRNA, ultimately improving myocardial thickness in the infarct. Delivery of the siMMP2 hydrogel led to significant functional improvements, including increased ejection fraction (27%, 66%), stroke volume (32%, 120%), and cardiac output (20%, 128%) when compared to controls (% increase versus hydrogels with control siRNA, % increase versus saline injection alone). This report demonstrates the utility of biomaterial-based RNA delivery systems for cardiac applications.

Recent advances in shear‐thinning and self‐healing hydrogels for biomedical applications

“…The controlled release of small molecules, proteins, and growth factors from CD‐based hydrogels has been widely investigated, whereas release kinetics can be tuned through porosity, mesh size, and degradation . More recently, CD‐based hydrogels were developed as gene carriers, including with β‐cyclodextrin‐modified polyethylenimine (PEI) and adamantane‐modified PEG for local siRNA release to the infarcted myocardium . The modified polymers assembled with siRNA to form hydrogels that released polyplexes for transfection.…”

HGF Treatment Promotes Cardiac Function and Cardiac Repair: Meta-analysis of Pig Models With Myocardial Infarction

“…In recent years, injectable hydrogels, a kind of promising synthetic biomaterials with advantages of mild gelation and cardiac-compatible properties [34,35], have been proved to improve cardiac function after local myocardial injection alone [36]. In addition, hydrogels can also encapsulate therapeutic drugs, deliver them to target areas, and subsequently achieve continuous therapeutic effects [37]. Therefore, hydrogels may become a kind of more attractive method of exogenous administration.…”

Gene Therapy with Hepatocyte Growth Factor Improves Left Ventricular Systolic Function After Myocardial Infarction: A Systematic Review and Meta-analysis of Pig Models

“…Recent studies have shown that the injection of hydrogel in ischaemic areas after MI could promote cardiac repair and improve cardiac function [42]. Hydrogels can also encapsulate therapeutic drugs and deliver them to target areas to achieve sustained therapeutic effects [43]. Steele et al [44] encapsulated two cytokines, dimeric fragment of HGF and engineered stromal cell-derived factor 1α, in hydrogels and delivered them to the peri-infarct regions, and found that the release time of the cytokines was signi cantly prolonged and the therapeutic effects were enhanced when the cytokines were encapsulated in hydrogels.…”