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Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition

Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodeling. While MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application due to the...

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Autores principales: Purcell, Brendan P., Lobb, David, Charati, Manoj B., Dorsey, Shauna M., Wade, Ryan J., Zellers, Kia N., Doviak, Heather, Pettaway, Sara, Logdon, Christina B., Shuman, James, Freels, Parker D., Gorman, Joseph H., Gorman, Robert C., Spinale, Francis G., Burdick, Jason A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031269/
https://www.ncbi.nlm.nih.gov/pubmed/24681647
http://dx.doi.org/10.1038/nmat3922
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author Purcell, Brendan P.
Lobb, David
Charati, Manoj B.
Dorsey, Shauna M.
Wade, Ryan J.
Zellers, Kia N.
Doviak, Heather
Pettaway, Sara
Logdon, Christina B.
Shuman, James
Freels, Parker D.
Gorman, Joseph H.
Gorman, Robert C.
Spinale, Francis G.
Burdick, Jason A.
author_facet Purcell, Brendan P.
Lobb, David
Charati, Manoj B.
Dorsey, Shauna M.
Wade, Ryan J.
Zellers, Kia N.
Doviak, Heather
Pettaway, Sara
Logdon, Christina B.
Shuman, James
Freels, Parker D.
Gorman, Joseph H.
Gorman, Robert C.
Spinale, Francis G.
Burdick, Jason A.
author_sort Purcell, Brendan P.
collection PubMed
description Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodeling. While MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application due 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 over-expression following a myocardial infarction (MI) significantly reduced MMP activity and attenuated adverse left ventricular remodeling in a porcine model of MI. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel.
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spelling pubmed-40312692014-12-01 Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition Purcell, Brendan P. Lobb, David Charati, Manoj B. Dorsey, Shauna M. Wade, Ryan J. Zellers, Kia N. Doviak, Heather Pettaway, Sara Logdon, Christina B. Shuman, James Freels, Parker D. Gorman, Joseph H. Gorman, Robert C. Spinale, Francis G. Burdick, Jason A. Nat Mater Article Inhibitors of matrix metalloproteinases (MMPs) have been extensively explored to treat pathologies where excessive MMP activity contributes to adverse tissue remodeling. While MMP inhibition remains a relevant therapeutic target, MMP inhibitors have not translated to clinical application due 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 over-expression following a myocardial infarction (MI) significantly reduced MMP activity and attenuated adverse left ventricular remodeling in a porcine model of MI. Our findings demonstrate that local, on-demand MMP inhibition is achievable through the use of an injectable and bioresponsive hydrogel. 2014-03-30 2014-06 /pmc/articles/PMC4031269/ /pubmed/24681647 http://dx.doi.org/10.1038/nmat3922 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Purcell, Brendan P.
Lobb, David
Charati, Manoj B.
Dorsey, Shauna M.
Wade, Ryan J.
Zellers, Kia N.
Doviak, Heather
Pettaway, Sara
Logdon, Christina B.
Shuman, James
Freels, Parker D.
Gorman, Joseph H.
Gorman, Robert C.
Spinale, Francis G.
Burdick, Jason A.
Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title_full Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title_fullStr Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title_full_unstemmed Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title_short Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
title_sort injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031269/
https://www.ncbi.nlm.nih.gov/pubmed/24681647
http://dx.doi.org/10.1038/nmat3922
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