Impaired wound healing that occurs in diabetics can result in many life-threatening complications associated with excessive expression of matrix metalloproteinases (MMPs), which mediate the proteolysis of major matrix constituents. In this study, the dendrimer polyamidoamine (PAMAM) and the polysaccharide hyaluronic acid (HA) were connected through the substrate polypeptide (Gly-PLGLAG-Cys) of MMP-2 to obtain the MMP-2-responsive nanocarrier HA-pep-PAMAM. Insoluble astragaloside (ASI) was encapsulated in this nanocarrier to achieve controlled release at the site of intractable wounds. The HA-pep-PAMAM-ASI was successfully prepared with an average diameter of 142.3 ± 28.9 nm. Immunohistochemical staining of the skin revealed that the hard-to-heal wounds of diabetic mice showed stronger expression of MMP-2 than the wounds of normal mice. HA-pep-PAMAM-ASI achieved 73.9% release in the presence of MMP-2, but only 13.5% in PBS. A dose-dependent effect of H₂O₂ on the proliferation of BJ and HaCaT cells was observed, and HA-pep-PAMAM-ASI treatment had the best antioxidant capacity with MMP-2 pretreatment. HA-pep-PAMAM-ASI significantly increased GSH levels and reduced reactive oxygen species (ROS) levels to achieve antioxidant effects. The MMP-2-pretreated HA-pep-PAMAM-ASI group showed more improved cell proliferation and migration abilities. Compared with ASI group, the expression of all wound-repair-related genes in the group of HA-pep-PAMAM-ASI was significantly increased, and HA-pep-PAMAM-ASI showed a pronounced in vivo therapeutic effect. Therefore, our results revealed that enzyme-responsive MMP-2-loaded PAMAM nanoparticles could promote wound healing in diabetes and may be a promising biomaterial for treatment.

中文翻译：

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用基质金属蛋白酶-2-响应性透明质酸末端缀合的聚酰胺酰胺树状聚合物包封黄芪甲苷可改善糖尿病的伤口愈合。

糖尿病患者伤口愈合不良会导致许多威胁生命的并发症，与基质金属蛋白酶（MMPs）的过度表达有关，而基质金属蛋白酶（MMPs）的表达会介导主要基质成分的蛋白水解。在这项研究中，通过MMP-2的底物多肽（Gly-PLGLAG-Cys）连接树状聚合物聚酰胺酰胺（PAMAM）和多糖透明质酸（HA），以获得MMP-2反应性纳米载体HA-pep-PAMAM。将不溶性黄芪甲苷（ASI）封装在该纳米载体中，以在顽固性伤口处实现受控释放。HA-pep-PAMAM-ASI已成功制备，平均直径为142.3±28.9 nm。皮肤的免疫组织化学染色显示，与正常小鼠相比，糖尿病小鼠难以治愈的伤口显示出更强的MMP-2表达。HA-pep-PAMAM-ASI在存在MMP-2的情况下达到73.9％的释放，但在PBS中仅为13.5％。观察到H 2 O 2对BJ和HaCaT细胞增殖的剂量依赖性作用，并且用MMP-2预处理对HA-pep-PAMAM-ASI处理具有最佳的抗氧化能力。HA-pep-PAMAM-ASI可显着提高GSH含量并降低活性氧（ROS）含量，以达到抗氧化作用。MMP-2预处理的HA-pep-PAMAM-ASI组显示出更高的细胞增殖和迁移能力。与ASI组相比，HA-pep-PAMAM-ASI组中所有伤口修复相关基因的表达均显着增加，而HA-pep-PAMAM-ASI组表达明显 MMP-2预处理对HA-pep-PAMAM-ASI的抗氧化能力最好。HA-pep-PAMAM-ASI可显着提高GSH含量并降低活性氧（ROS）含量，以达到抗氧化作用。MMP-2预处理的HA-pep-PAMAM-ASI组显示出更高的细胞增殖和迁移能力。与ASI组相比，HA-pep-PAMAM-ASI组中所有伤口修复相关基因的表达均显着增加，而HA-pep-PAMAM-ASI组表达明显 MMP-2预处理对HA-pep-PAMAM-ASI的抗氧化能力最好。HA-pep-PAMAM-ASI可显着提高GSH含量并降低活性氧（ROS）含量，以达到抗氧化作用。MMP-2预处理的HA-pep-PAMAM-ASI组显示出更高的细胞增殖和迁移能力。与ASI组相比，HA-pep-PAMAM-ASI组中所有伤口修复相关基因的表达均显着增加，而HA-pep-PAMAM-ASI组表达明显体内治疗作用。因此，我们的研究结果表明，负载酶反应性MMP-2的PAMAM纳米颗粒可以促进糖尿病的伤口愈合，并且可能是有前途的生物治疗材料。