Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction.
Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction.
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持续释放基于肽的基质金属蛋白酶 2 抑制剂可减轻心肌梗死后的不良心脏重塑并改善心脏功能
DOI：
10.1021/acs.biomac.7b00760
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发表时间：
2017-09-11
影响因子：
6.2
通讯作者：
Guan J
中科院分区：
文献类型：
--
作者：
Fan Z;Fu M;Xu Z;Zhang B;Li Z;Li H;Zhou X;Liu X;Duan Y;Lin PH;Duann P;Xie X;Ma J;Liu Z;Guan J
心肌梗死（MI）后，细胞外基质（ECM）被基质金属蛋白酶（MMP）特别是MMP-2的上调降解，降低了组织的力学性能，导致心功能恶化。心肌梗死早期心肌细胞外基质降解的减弱有可能保护组织的力学性能，从而增加心脏功能。然而，有效预防心脏ECM降解的策略仍有待建立。目前的临床前方法由于分配给心脏组织的药物剂量低、剂量限制性副作用和心脏纤维化而显示出有限的疗效。为了解决这些局限性，我们已经开发了一种MMP-2抑制剂递送系统，该系统可以在MI的早期阶段特异性地递送到梗死心脏中，以有效地防止MMP-2介导的ECM降解。该系统是基于可注射的，可降解的，快速凝胶化和热敏性水凝胶，和MMP-2特异性抑制剂，肽CTTHWGFTLC（CTT）。使用快速凝胶化水凝胶可以将CTT完全保留在心脏组织中。该系统能够在4周内释放低分子量CTT，这可能是由于水凝胶和CTT之间的强氢键。释放动力学通过加载到水凝胶中的CTT的量来调节，并且使用可以与CTT和水凝胶相互作用的硫酸软骨素和肝素。这两种糖胺聚糖增强CTT的释放，而肝素更大大加速释放。在注射到梗塞心脏4周后，释放的CTT有效地防止了心脏ECM降解，因为它不仅增加了组织厚度，而且还保留了与正常心脏组织相似的胶原蛋白组成。此外，输送系统显著改善了心脏功能。重要的是，输送系统不会诱导心脏纤维化。这些结果表明，所开发的MMP-2抑制剂递送系统具有有效地减少不利的心肌重构和改善心脏功能的潜力。
Following myocardial infarction (MI), degradation of extracellular matrix (ECM) by upregulated matrix metalloproteinases (MMPs) especially MMP-2 decreases tissue mechanical properties, leading to cardiac function deterioration. Attenuation of cardiac ECM degradation at the early stage of MI has the potential to preserve tissue mechanical properties, resulting in cardiac function increase. Yet the strategy for efficiently preventing cardiac ECM degradation remains to be established. Current preclinical approaches have shown limited efficacy due to low drug dosage allocated to the heart tissue, dose-limiting side effects, and cardiac fibrosis. To address these limitations, we have developed a MMP-2 inhibitor delivery system that can be specifically delivered into infarcted hearts at early stage of MI to efficiently prevent MMP-2-mediated ECM degradation. The system was based on an injectable, degradable, fast gelation and thermosensitive hydrogel, and a MMP-2 specific inhibitor, peptide CTTHWGFTLC (CTT). The use of fast gelation hydrogel allowed to completely retain CTT in the heart tissue. The system was able to release low molecular weight CTT over 4 weeks possibly due to the strong hydrogen bonding between the hydrogel and CTT. The release kinetics was modulated by amount of CTT loaded into the hydrogel, and using chondroitin sulfate and heparin that can interact with CTT and the hydrogel. Both glycosaminoglycans augmented CTT release while heparin more greatly accelerated the release. After injecting into the infarcted hearts for 4 weeks, the released CTT efficiently prevented cardiac ECM degradation as it not only increased tissue thickness, but also preserved collagen composition similar to that in the normal heart tissue. In addition, the delivery system significantly improved cardiac function. Importantly, the delivery system did not induce cardiac fibrosis. These results demonstrate that the developed MMP-2 inhibitor delivery system has potential to efficiently reduce adverse myocardial remodeling and improve cardiac function.
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pH 敏感和热敏感水凝胶作为心脏治疗的干细胞载体
影响因子：
9.5
作者：
Li Z;Fan Z;Xu Y;Lo W;Wang X;Niu H;Li X;Xie X;Khan M;Guan J
通讯作者：
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影响因子：
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发表时间：
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影响因子：
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