Myocardial-Infarction-Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On-Demand Growth Factor Delivery

Abstract

Although in situ restoration of blood supply to the infarction region and attenuating pre-existing extracellular matrix degradation remain potential therapeutic approaches for myocardial infarction (MI), local delivery of therapeutics has been limited by low accumulation (inefficacy) and unnecessary diffusion (toxicity). Here, a dual functional MI-responsive hydrogel is fabricated for on-demand drug delivery to promote angiogenesis and inhibit cardiac remodeling by targeting upregulated matrix metalloproteinase-2/9 (MMP-2/9) after MI. A glutathione (GSH)-modified collagen hydrogel (collagen-GSH) is prepared by conjugating collagen amine groups with GSH sulfhydryl groups and the recombinant protein GST-TIMP-bFGF (bFGF: basic fibroblast growth factor) by fusing bFGF with glutathione-S-transferase (GST) and MMP-2/9 cleavable peptide PLGLAG (TIMP). Specific binding between GST and GSH significantly improves the amount of GST-TIMP-bFGF loaded in collagen-GSH hydrogel. The TIMP peptide enclosed between GST and bFGF responds to MMPs for on-demand release during MI. Additionally, the TIMP peptide is a competitive substrate of MMPs that inhibits the excessive degradation of cardiac matrix by MMPs after MI. GST-TIMP-bFGF/collagen-GSH hydrogels promote the recovery of MI rats by enhancing vascularization and ameliorating myocardium remodeling. The results suggest that on-demand growth factor delivery by synchronously controlling binding and responsive release to promote angiogenesis and attenuate cardiac remodeling might be promising for the treatment of ischemic heart disease.

Keywords: basic fibroblast growth factor; hydrogels; matrix metalloproteinases; microenvironment response; myocardial infarction.