An MMP-degradable and conductive hydrogel to stabilize HIF-1α for recovering cardiac functions

• Published in: Theranostics Vol. 12; no. 1; pp. 127 - 142
• Main Authors: Wei, Xiaojuan, Chen, Si, Xie, Tian, Chen, Hongchi, Jin, Xin, Yang, Jumin, Sahar, Shafaq, Huang, Huanlei, Zhu, Shuoji, Liu, Nanbo, Yu, Changjiang, Zhu, Ping, Wang, Wei, Zhang, Wei
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 2022; Ivyspring International Publisher
• Subjects: Animals; Biomedical materials; Cell Line; Dopamine; Ethanol; Fibroblasts; Fourier transforms; Heart; Hyaluronic acid; Hydrogels; Hydrogels - therapeutic use; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Matrix Metalloproteinases - therapeutic use; Mice; Myocardial Infarction - therapy; Nanoparticles; NMR; Nuclear magnetic resonance; Polyethylene glycol; Polymerization; Rats; Rats, Sprague-Dawley; Research Paper; Transplants & implants; injectable hydrogel; matrix metalloproteinase; hypoxia-inducible factor-1α; conductivity; myocardial infarction
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.63481

Although a few injectable hydrogels have shown a reliable biosafety and a moderate promise in treating myocardial infarction (MI), the updated hydrogel systems with an on-demand biodegradation and multi-biofunctions to deliver therapeutic drug would achieve more prominent efficacy in the future applications. In this report, a conductive and injectable hydrogel crosslinked by matrix metalloproteinase-sensitive peptides (MMP-SP) was rationally constructed to stabilize hypoxia-inducible factor-1α (HIF-1α) to recover heart functions after MI. Firstly, tetraaniline (TA) was incorporated into partially oxidized alginate (ALG-CHO) to endow the hydrogels with conductivity. The 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) nanodrug was manufactured with high drug loading capacity and decorated with polymerized dopamine (PDA) to achieve a stable release of the drug. Both ALG-CHO and DPCA@PDA can be cross-linked by thiolated hyaluronic acid (HA-SH) and thiolated MMP-SP to construct a MMP-degradable and conductive hydrogel. After administration in the infarcted heart of rats, echocardiographic assessments, histological evaluation, and RT-PCR were used to evaluate therapeutic effects of hydrogels. The cell viability and the results of subcutaneous implantation verify a good cytocompatibility and biocompatibility of the resulting hydrogels. The hydrogel shows remarkable strength in decreasing the expression of inflammatory factors, maintaining a high level of HIF-1α to promote the vascularization, and promoting the expression of junctional protein connexin 43. Meanwhile, the multifunctional hydrogels greatly reduce the infarcted area (by 33.8%) and improve cardiac functions dramatically with ejection fraction (EF) and fractional shortening (FS) being increased by 31.3% and 19.0%, respectively. The as-prepared hydrogels in this report achieve a favorable therapeutic effect, offering a promising therapeutic strategy for treating heart injury.