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Myocardial‐Infarction‐Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On‐Demand Growth Factor Delivery
Author(s) -
Fan Caixia,
Shi Jiajia,
Zhuang Yan,
Zhang Lulu,
Huang Lei,
Yang Wen,
Chen Bing,
Chen Yanyan,
Xiao Zhifeng,
Shen He,
Zhao Yannan,
Dai Jianwu
Publication year - 2019
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201902900
Subject(s) - matrix metalloproteinase , basic fibroblast growth factor , angiogenesis , glutathione , extracellular matrix , matrix metalloproteinase inhibitor , therapeutic angiogenesis , pharmacology , self healing hydrogels , growth factor , tissue inhibitor of metalloproteinase , materials science , microbiology and biotechnology , chemistry , neovascularization , biochemistry , medicine , biology , receptor , enzyme , polymer chemistry
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.