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 Oct 18;9(41):35628-35641. doi: 10.1021/acsami.7b11846. Epub 2017 Oct 4.
Cu-BTTri (HBTTri = 1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene) is a water-stable, copper-based metal-organic framework (MOF) that exhibits the ability to generate therapeutic nitric oxide (NO) from S-nitrosothiols (RSNOs) available within the bloodstream. Immobilization of Cu-BTTri within a polymeric membrane may allow for localized NO generation at the blood-material interface. This work demonstrates that Cu-BTTri can be incorporated within hydrophilic membranes prepared from poly(vinyl alcohol) (PVA), a polymer that has been examined for numerous biomedical applications. Following immobilization, the ability of the MOF to produce NO from the endogenous RSNO S-nitrosoglutathione (GSNO) is not significantly inhibited. Poly(vinyl alcohol) membranes containing dispersions of Cu-BTTri were tested for their ability to promote NO release from a 10 μM initial GSNO concentration at pH 7.4 and 37 °C, and NO production was observed at levels associated with antithrombotic therapeutic effects without significant copper leaching (<1%). Over 3.5 ± 0.4 h, 10 wt % Cu-BTTri/PVA membranes converted 97 ± 6% of GSNO into NO, with a maximum NO flux of 0.20 ± 0.02 nmol·cm·min. Furthermore, it was observed for the first time that Cu-BTTri is capable of inducing NO production from GSNO under aerobic conditions. At pH 6.0, the NO-forming reaction of 10 wt % Cu-BTTri/PVA membrane was accelerated by 22%, while an opposite effect was observed in the case of aqueous copper(II) chloride. Reduced temperature (20 °C) and the presence of the thiol-blocking reagent N-ethylmaleimide (NEM) impair the NO-forming reaction of Cu-BTTri/PVA with GSNO, with both conditions resulting in a decreased NO yield of 16 ± 1% over 3.5 h. Collectively, these findings suggest that Cu-BTTri/PVA membranes may have therapeutic utility through their ability to generate NO from endogenous substrates. Moreover, this work provides a more comprehensive analysis of the parameters that influence Cu-BTTri efficacy, permitting optimization for potential medical applications.
Cu-BTTri（HBTTri=1,3,5-三[1H-1,2,3-三唑-5-基]苯）是一种水稳定的铜基金属有机骨架（MOF），能够从血液中可用的 S-亚硝硫醇（RSNO）中产生治疗性一氧化氮（NO）。将 Cu-BTTri 固定在聚合物膜内可能允许在血液-材料界面处局部产生 NO。这项工作表明，Cu-BTTri 可以掺入由聚乙烯醇（PVA）制备的亲水性膜中，PVA 已被用于许多生物医学应用。固定化后，MOF 从内源性 RSNO S-亚硝酰谷胱甘肽（GSNO）产生 NO 的能力没有受到显著抑制。含有 Cu-BTTri 分散体的聚乙烯醇膜被测试了从初始 10 μM GSNO 浓度在 pH 7.4 和 37°C 下释放 NO 的能力，并且在与抗血栓治疗效果相关的水平下观察到了 NO 产生，而没有明显的铜浸出（<1%）。在 3.5±0.4 小时内，10wt%Cu-BTTri/PVA 膜将 97±6%的 GSNO 转化为 NO，最大 NO 通量为 0.20±0.02nmol·cm·min。此外，首次观察到 Cu-BTTri 能够在有氧条件下诱导 GSNO 产生 NO。在 pH 6.0 下，10wt%Cu-BTTri/PVA 膜的 NO 形成反应加速了 22%，而在铜(II)氯化物的情况下则观察到相反的效果。降低温度（20°C）和存在硫醇阻断试剂 N-乙基马来酰亚胺（NEM）会损害 Cu-BTTri/PVA 与 GSNO 的 NO 形成反应，在 3.5 小时内，这两种情况都会导致 NO 产量下降 16±1%。总的来说，这些发现表明，Cu-BTTri/PVA 膜通过从内源性底物产生 NO 可能具有治疗用途。此外，这项工作提供了对影响 Cu-BTTri 功效的参数的更全面分析，允许为潜在的医学应用进行优化。
