Biomedical Engineering Department, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
International Institute for Nanotechnology, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
ACS Nano. 2018 Feb 27;12(2):1023-1032. doi: 10.1021/acsnano.7b01850. Epub 2018 Feb 12.
The successful treatment of chronic nonhealing wounds requires strategies that promote angiogenesis, collagen deposition, and re-epithelialization of the wound. Copper ions have been reported to stimulate angiogenesis; however, several applications of copper salts or oxides to the wound bed are required, leading to variable outcomes and raising toxicity concerns. We hypothesized that copper-based metal-organic framework nanoparticles (Cu-MOF NPs), referred to as HKUST-1, which are rapidly degraded in protein solutions, can be modified to slowly release Cu, resulting in reduced toxicity and improved wound healing rates. Folic acid was added during HKUST-1 synthesis to generate folic-acid-modified HKUST-1 (F-HKUST-1). The effect of folic acid incorporation on NP stability, size, hydrophobicity, surface area, and copper ion release profile was measured. In addition, cytotoxicity and in vitro cell migration processes due to F-HKUST-1 and HKUST-1 were evaluated. Wound closure rates were assessed using the splinted excisional dermal wound model in diabetic mice. The incorporation of folic acid into HKUST-1 enabled the slow release of copper ions, which reduced cytotoxicity and enhanced cell migration in vitro. In vivo, F-HKUST-1 induced angiogenesis, promoted collagen deposition and re-epithelialization, and increased wound closure rates. These results demonstrate that folic acid incorporation into HKUST-1 NPs is a simple, safe, and promising approach to control Cu release, thus enabling the direct application of Cu-MOF NPs to wounds.
慢性难愈性创面的成功治疗需要采用多种策略以促进血管生成、胶原沉积和创面再上皮化。已有研究报道铜离子可刺激血管生成；然而，为了达到预期效果，需要将铜盐或铜氧化物多次应用于创面，这会导致结果的可变性，并引发毒性问题。我们假设铜基金属有机骨架纳米粒子（Cu-MOF NPs），即 HKUST-1，在蛋白质溶液中可迅速降解，通过对其进行修饰可实现铜的缓慢释放，从而降低毒性并提高创面愈合率。在 HKUST-1 的合成过程中加入叶酸以生成叶酸修饰的 HKUST-1（F-HKUST-1）。我们对叶酸的加入对 NP 稳定性、粒径、疏水性、比表面积和铜离子释放特性的影响进行了测量。此外，还评估了 F-HKUST-1 和 HKUST-1 的细胞毒性和体外细胞迁移过程。利用糖尿病小鼠的有夹板的皮肤切开创面模型评估创面闭合率。将叶酸纳入 HKUST-1 后可实现铜离子的缓慢释放，从而降低细胞毒性并增强体外细胞迁移。在体内，F-HKUST-1 可诱导血管生成，促进胶原沉积和再上皮化，并提高创面闭合率。这些结果表明，将叶酸纳入 HKUST-1 NPs 是一种简单、安全且很有前途的控制 Cu 释放的方法，从而使 Cu-MOF NPs 可直接应用于创面。
