Department of Chemistry, ‡School of Biomedical Engineering, and §Chemical and Biological Engineering, Colorado State University , Fort Collins, Colorado 80523, United States.
ACS Appl Mater Interfaces. 2017 Feb 15;9(6):5139-5148. doi: 10.1021/acsami.6b14937. Epub 2017 Feb 6.
It has been previously demonstrated that copper-based metal-organic frameworks (MOFs) accelerate formation of the therapeutically active molecule nitric oxide (NO) from S-nitrosothiols (RSNOs). Because RSNOs are naturally present in blood, this function is hypothesized to permit the controlled production of NO through use of MOF-based blood-contacting materials. The practical implementation of MOFs in this application typically requires incorporation within a polymer support, yet this immobilization has been shown to impair the ability of the MOF to interact with the NO-forming RSNO substrate. Here, the water-stable, copper-based MOF H[(CuCl)-(BTTri)] (HBTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), or Cu-BTTri, was incorporated within the naturally derived polysaccharide chitosan to form membranes that were evaluated for their ability to enhance NO generation from the RSNO S-nitrosoglutathione (GSNO). This is the first report to evaluate MOF-induced NO release from GSNO, the most abundant small-molecule RSNO. At a 20 μM initial GSNO concentration (pH 7.4 phosphate buffered saline, 37 °C), chitosan/Cu-BTTri membranes induced the release of 97 ± 3% of theoretical NO within approximately 4 h, corresponding to a 65-fold increase over the baseline thermal decomposition of GSNO. Furthermore, incorporation of Cu-BTTri within hydrophilic chitosan did not impair the activity of the MOF, unlike earlier efforts using hydrophobic polyurethane or poly(vinyl chloride). The reuse of the membranes continued to enhance NO production from GSNO in subsequent experiments, suggesting the potential for continued use. Additionally, the major organic product of Cu-BTTri-promoted GSNO decomposition was identified as oxidized glutathione via mass spectrometry, confirming prior hypotheses. Structural analysis by pXRD and assessment of copper leaching by ICP-AES indicated that Cu-BTTri retains crystallinity and exhibits no significant degradation following exposure to GSNO. Taken together, these findings provide insight into the function and utility of polymer/Cu-BTTri systems and may support the development of future MOF-based biomaterials.
先前已经证明，基于铜的金属有机骨架（MOF）可以加速从 S-亚硝基硫醇（RSNO）中形成治疗上有效的分子一氧化氮（NO）。因为 RSNO 自然存在于血液中，所以假设这种功能可以通过使用基于 MOF 的与血液接触的材料来控制 NO 的产生。在这种应用中，MOF 的实际实施通常需要包含在聚合物载体中，但是已经证明这种固定化会损害 MOF 与形成 NO 的 RSNO 底物相互作用的能力。在这里，将水稳定的基于铜的 MOF H[(CuCl)-(BTTri)]（HBTTri = 1,3,5-三（1H-1,2,3-三唑-5-基）苯）或 Cu-BTTri 掺入天然衍生多糖壳聚糖中以形成膜，然后评估它们从 RSNO S-亚硝基谷胱甘肽（GSNO）增强 NO 生成的能力。这是第一个评估 MOF 诱导的 GSNO 中 NO 释放的报告，GSNO 是最丰富的小分子 RSNO。在初始 GSNO 浓度为 20 μM（pH 7.4 磷酸盐缓冲盐水，37°C）时，壳聚糖/Cu-BTTri 膜在大约 4 小时内诱导释放了 97±3%的理论 NO，与 GSNO 的基线热分解相比增加了 65 倍。此外，与早期使用疏水性聚氨酯或聚氯乙烯的研究不同，将 Cu-BTTri 掺入亲水性壳聚糖中不会损害 MOF 的活性。在随后的实验中，膜的重复使用继续增强了 GSNO 产生的 NO，这表明可以继续使用。此外，通过质荷比质谱鉴定了 Cu-BTTri 促进 GSNO 分解的主要有机产物为氧化谷胱甘肽，这证实了先前的假设。通过 pXRD 进行的结构分析和通过 ICP-AES 评估的铜浸出表明，Cu-BTTri 在暴露于 GSNO 后保留了结晶度，并且没有明显降解。总之，这些发现为聚合物/Cu-BTTri 系统的功能和实用性提供了深入的了解，并可能支持未来基于 MOF 的生物材料的发展。
