Nitric Oxide Generation on Demand for Biomedical Applications via Electrocatalytic Nitrite Reduction by Copper BMPA- and BEPA-Carboxylate Complexes

Abstract

Intravascular (IV) catheters are essential devices in the hospital that are used to monitor a patient’s blood and for administering drugs or nutrients. However, IV catheters are also prone to blood clotting at the point of insertion and infection by formation of robust bacterial biofilms on their surface. Nitric oxide (NO) is ideally suited to counteract both of these problems, due to its ability to inhibit platelet activation/aggregation and its antimicrobial properties. One way to equip catheters with NO releasing properties is by electrocatalytic nitrite reduction to NO by copper complexes in a multilumen configuration. In this work, we systematically investigate six closely related Cu­(II) BMPA- and BEPA-carboxylate complexes (BMPA = bis­(2-methylpyridyl)­amine); BEPA = bis­(2-ethylpyridyl)­amine), using carboxylate groups of different chain lengths. The corresponding Cu­(II) complexes were characterized using UV–vis, EPR spectroscopy, and X-ray crystallography. Using detailed cyclic voltammetry (CV) and bulk electrocatalyic studies (with real-time NO quantification), in aqueous media, pH 7.4, we are able to derive clear reactivity relations between the ligand structures of the complexes, their Faradaic efficiencies for NO generation, their turnover frequencies (TOFs), and their redox potentials. Our results show that the complex [Cu­(BEPA-Bu)]­(OAc) is the best catalyst with a high Faradaic efficiency over large nitrite concentration ranges and the expected best tolerance to oxygen levels. For this species, the more positive reduction potential suppresses NO disproportionation, which is a major Achilles heel of the (faster) catalysts with the more negative reduction potentials.

Endothelium-Mimicking Multifunctional Coating Modified Cardiovascular Stents via a Stepwise Metal-Catechol-(Amine) Surface Engineering Strategy

“…By changing the coating thickness, stable NO production at physiological levels was extended to 2 weeks [32]. Recently, several Cu(II)-ligand complexes were investigated to endow intravascular catheters with on demand NO generation for thromboresistant and antimicrobial performance [63,64]. The efficiency and stability of NO generation were well compared by equipping catheters with different Cu(II)-ligand complexes through electrocatalytic nitrite reduction.…”

Azanone (HNO): generation, stabilization and detection

“…[60][61][62][63] Nitric oxide, for example, has already been successfully used as an inhaled therapeutic agent to treat cardiac as well as respiratory conditions, to the point of reducing the need for assisted respiration in some cases. [64][65][66][67][68][69][70]…”

Minimising Blood Stream Infection: Developing New Materials for Intravascular Catheters

“…Putting the issue of dwell time aside, the release of antibiotic moieties (i.e., rifampicin) have a long history but the increasing threat of bacterial resistance has driven considerable effort to examine alternative antimicrobial agents. Various antimicrobial peptides [100,108,[113][114][115], guanidine derivatives (i.e., poly hexamethyl biguanide, polyarginines) [103,104], quaternary ammonium compounds [96,98], nitric oxide precursors [105,106,116,117], silver [118][119][120] and a host of other small molecules/metal ions or nanoparticles [107,110,118,[121][122][123][124] with possible biocidal activity have all been investigated as potential modifiers for use in catheters and, while these invariably impact bacterial colonisation, they have yet to make the leap to commercial exploitation and/or substantive clinical trials.…”

“…The smart approach, as indicated previously, is not necessarily limited to diagnostics but can also be harnessed to yield an "on demand" antimicrobial action. In addition to the generation of ROS, reactive nitrogen species (RNS) have also been considered and several reports have targeted the selective release of nitric oxide (NO) as the principal weapon through which to prevent bacterial colonisation [105,106,116,117]. Such work builds on the fact that NO is a chemical transmitter which has a multitude of biochemical roles but, in this context, its status as a key player in minimising platelet adhesion whilst also acting as a broad spectrum antimicrobial is of greatest value.…”

“…The electrochemical generation of NO represents a new stage in the evolution of active catheters and various reports have examined its electrocatalytic generation from nitrite [ 116 , 117 ]. A variety of copper complexes have been investigated as potential redox cyclers (indicated in Figure 6 B).…”