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.
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Acknowledgements
The authors would like to thank T. Lee from Amgen, for supplying the rTIMP-3 peptide used in this study, and W. Liu, S. Pickup and W. Witschey, from Penn Medicine, for MRI technical expertise. This work was financially supported by the National Institutes of Health (R01 HL107938, HL111090, HL095608, T32 HL007954), and a Veterans’ Affairs Health Administration Merit Award (5101BX000168-03) to F.G.S.
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B.P.P., M.B.C., R.C.G., F.G.S. and J.A.B. conceived the ideas and designed the experiments. B.P.P., D.L., M.B.C., S.M.D., R.J.W., K.N.Z., H.D., S.P., C.B.L., J.A.S. and P.D.F. conducted the experiments and analysed the data. B.P.P., J.H.G., R.C.G, F.G.S. and J.A.B. interpreted the data and wrote the manuscript.
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Purcell, B., Lobb, D., Charati, M. et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nature Mater 13, 653–661 (2014). https://doi.org/10.1038/nmat3922
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DOI: https://doi.org/10.1038/nmat3922
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