A Sequential Dual Functional Supramolecular Hydrogel with Promoted Drug Release to Scavenge ROS and Stabilize HIF-1α for Myocardial Infarction Treatment.

Abstract

Myocardial infarction (MI) has a characteristic inflammatory microenvironment due to the overproduction of reactive oxygen species (ROS) and causes the extraordinary deposition of collagen and thereby fibrosis. An on-demand adaptive drug releasing hydrogel is designed to modulate the inflammatory microenvironment and inhibit cardiac fibroblasts (CFs) proliferation post MI by scavenging the overproduced ROS and releasing 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) to maintain the expression of hypoxia-inducible factor 1α (HIF-1α). DPCA is prefabricated to a prodrug linked with disulfide bond (DPCA-S-S-OH). The DPCA-S-S-OH and carboxylated calixarene (CSAC4A) are grafted onto the backbone of methacrylated hyaluronic acid (HAMA) to obtain HAMA-S-S-DPCA and HAMA-CA, respectively, which are further reacted to form a dual network hydrogel (R⁺ /DPCA(CA)) with covalent linking and host-guest interaction between DPCA and CSAC4A. The ROS-triggered hydrolysis of ester bond and subsequently sustaining release of DPCA from the cavity of CSAC4A jointly cause the constant expression of HIF-1α, which significantly restricts the CFs proliferation, leading to suppressed fibrosis and promoted heart repair.