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- Title
Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.
- Authors
Purcell, Brendan P.; Lobb, David; Charati, Manoj B.; Dorsey, Shauna M.; Wade, Ryan J.; Zellars, Kia N.; Doviak, Heather; Pettaway, Sara; Logdon, Christina B.; Shuman, James A.; Freels, Parker D.; Gorman III, Joseph H.; Gorman, Robert C.; Spinale, Francis G.; Burdick, Jason A.
- Abstract
Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodelling. Although MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application owing to the dose-limiting side effects following systemic administration of the drugs. Here, we describe the synthesis of a polysaccharide-based hydrogel that can be locally injected into tissues and releases a recombinant tissue inhibitor of MMPs (rTIMP-3) in response to MMP activity. Specifically, rTIMP-3 is sequestered in the hydrogels through electrostatic interactions and is released as crosslinks are degraded by active MMPs. Targeted delivery of the hydrogel/rTIMP-3 construct to regions of MMP overexpression following a myocardial infarction significantly reduced MMP activity and attenuated adverse left ventricular remodelling in a porcine model of myocardial infarction. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.
- Subjects
COLLOIDS in medicine; MATRIX metalloproteinases; TISSUE remodeling; TISSUE inhibitors of metalloproteinases; CROSSLINKING (Polymerization); ELECTROSTATIC interaction; MYOCARDIAL infarction; DRUG administration
- Publication
Nature Materials, 2014, Vol 13, Issue 6, p653
- ISSN
1476-1122
- Publication type
Article
- DOI
10.1038/nmat3922