Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.
Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition.
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DOI：
10.1038/nmat3922
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发表时间：
2014-06
期刊：
影响因子：
41.2
通讯作者：
Burdick, Jason A.
中科院分区：
文献类型：
--
作者：
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, Joseph H., III;Gorman, Robert C.;Spinale, Francis G.;Burdick, Jason A.
基质金属蛋白酶（MMP）的抑制剂已被广泛探索以治疗其中过度MMP活性导致不良组织重塑的病理。虽然MMP抑制仍然是一个相关的治疗目标，MMP抑制剂尚未转化为临床应用，由于剂量限制性的副作用后，全身给药的药物。在这里，我们描述了一种基于多糖的水凝胶的合成，该水凝胶可以局部注射到组织中，并响应于MMP活性释放重组MMP组织抑制剂（rTIMP-3）。具体而言，rTIMP-3通过静电相互作用被隔离在水凝胶中，并随着交联被活性MMP降解而释放。在猪MI模型中，将水凝胶/rTIMP-3构建体靶向递送至心肌梗死（MI）后MMP过表达的区域显著降低了MMP活性并减弱了不利的左心室重构。我们的研究结果表明，局部，按需MMP抑制是通过使用可注射和生物响应水凝胶实现的。
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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影响因子：
37.8
作者：
Segers, Vincent F. M.;Tokunou, Tomotake;Lee, Richard T.
通讯作者：
Lee, Richard T.
影响因子：
20.1
作者：
King, MK;Coker, ML;Spinale, FG
通讯作者：
Spinale, FG
DOI：
10.1073/pnas.0737381100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Lutolf, MP;Lauer-Fields, JL;Hubbell, JA
通讯作者：
Hubbell, JA
影响因子：
6.2
作者：
Kim, S;Healy, KE
通讯作者：
Healy, KE
影响因子：
4.8
作者：
Lee, Meng-Huee;Atkinson, Susan;Murphy, Gillian
通讯作者：
Murphy, Gillian