Monitoring a MOF Catalyzed Reaction Directly in Blood Plasma

Abstract

Herein, we establish a method to quantitatively monitor a metal–organic framework (MOF)-catalyzed, biomedically relevant reaction directly in blood plasma, specifically, the generation of nitric oxide (NO) from the endogenous substrate S-nitrosoglutathione (GSNO) catalyzed by H3[(Cu4Cl)3–(BTTri)8] (CuBTTri). The reaction monitoring method uses UV–vis and 1H NMR spectroscopies along with a nitric oxide analyzer (NOA) to yield the reaction stoichiometry and catalytic rate for GSNO to NO conversion catalyzed by CuBTTri in blood plasma. The results show 100% loss of GSNO within 16 h and production of 1 equiv. of glutathione disulfide (GSSG) per 2 equiv. of GSNO. Only 78 ± 10% recovery of NO­(g) was observed, indicating that blood plasma can scavenge the generated NO before it can escape the reaction vessel. Significantly, to best apply and understand reaction systems with biomedical importance, such as NO release catalyzed by CuBTTri, methods to study the reaction directly in biological solvents must be developed.

Computational Insights into the Mechanism of Nitric Oxide Generation from S-Nitrosoglutathione Catalyzed by a Copper Metal–Organic Framework

“…The computational studies answered critical questions that remained from the experimental work and provided thermodynamic evidence expanding the previously proposed mechanism involving only Cu­(II) and a single GSNO in the catalytic cycle. The currently proposed S-complexed Cu­(I) mechanism is consistent with all of the available experimental evidence. − This mechanism invokes GSH coordination to copper through its sulfur atom as well as a Cu­(I) intermediate. The computational studies also elucidated the critical role of protons and their probable sites of action in the mechanism.…”

“…Water-stable catalytic generation of nitric oxide (NO) from endogenous sources has great potential for applications in biomedical implants, where NO release from the implant is known to have desirable vasodilatory and other beneficial health effects. − The Cu-1,3,5-tris­[1 H -1,2,3-triazol-5-yl]­benzene (Cu-BTTri) metal–organic framework (MOF) − has been shown to catalyze the homolytic sulfur–nitrogen cleavage of S -nitrosoglutathione (GSNO) in the presence of glutathione (GSH) to produce NO and glutathione disulfide (GSSG) in aqueous solutions. Given its stability and catalytic activity in both water and blood, − the solid-state Cu-BTTri catalyst is well-suited for biomedical applications …”

“…Recent experimental investigation − into the kinetics of Cu-BTTri-catalyzed NO production from GSNO revealed several key elements. First, a reaction stoichiometry of 2GSNO → 2NO + GSSG in aqueous solution (Figure ) was established by direct NMR monitoring in aqueous solution .…”

MOF Polymer Composites Exhibit Faster Nitric Oxide Catalysis than MOF Crystallites

“…The CuBTTri powder initially shows a burst of NO generation followed by first order exponential decay, which is well in line with previous reports for several different Cu-MOF powder catalyzed NO generation systems. 6,19,20,23 The low level of NO generated by the powder in Figure 3 is explained by the fact that only trace GSH is present in the reactions for Figure 3. The powder also initially (within approximately 15 min) releases more NO than the composite.…”

“…Recent research has focused on solving the problem of clot formation via the use of thromboresistant materials as an alternative to the administration of systemic anticoagulants. − Materials that release nitric oxide (NO) at the surface of a device have been shown to prevent the adhesion of cells that can lead to a thrombus. − One potential strategy to achieve localized NO release is to use a material capable of generating NO from a class of endogenous NO donors called S -nitrosothiols (RSNOs, Figure ). − Our group has established that the copper-based metal–organic framework (MOF) H 3 [(Cu 4 Cl) 3 (BTTri) 8 ] (CuBTTri, Figure ) catalyzes the oxidation of S -nitrosoglutathione (GSNO) to yield NO and glutathione disulfide (GSSG). − CuBTTri has been shown to catalyze GSNO oxidation both as an unprocessed powder and when embedded in medical grade polymers. ,, However, the two systems have not yet been directly compared to investigate how embedding CuBTTri within a polymer matrix impacts its behavior as a heterogeneous NO release catalyst …”