Enzyme Mimics for the Catalytic Generation of Nitric Oxide from Endogenous Prodrugs

Abstract

The highly diverse biological roles of nitric oxide (NO) in both physiological and pathophysiological processes have prompted great interest in the use of NO as a therapeutic agent in various biomedical applications. NO can exert either protective or deleterious effects depending on its concentration and the location where it is delivered or generated. This double-edged attribute, together with the short half-life of NO in biological systems, poses a major challenge to the realization of the full therapeutic potential of this molecule. Controlled release strategies show an admirable degree of precision with regards to the spatiotemporal dosing of NO but are disadvantaged by the finite NO deliverable payload. In turn, enzyme-prodrug therapy techniques afford enhanced deliverable payload but are troubled by the inherent low stability of natural enzymes, as well as the requirement to control pharmacokinetics for the exogenous prodrugs. The past decade has seen the advent of a new paradigm in controlled delivery of NO, namely localized bioconversion of the endogenous prodrugs of NO, specifically by enzyme mimics. These early developments are presented, successes of this strategy are highlighted, and possible future work on this avenue of research is critically discussed.

Polymeric Nitric Oxide Delivery Nanoplatforms for Treating Cancer, Cardiovascular Diseases, and Infection

“…The application of copper‐based enzyme mimics in catalytic generation of NO from endogenous prodrugs has been well documented. [ 8 ] GSNO and S‐nitroso‐ N ‐acetylpenicillamine (SNAP) are two commonly used SNOs that have been intensively studied in a variety of biomedical applications. [ 12b ] SNOs can also be synthesized chemically by reacting thiols with nitrous acid.…”

“…Therefore, special attentions and careful considerations are needed in designing NO delivery system that can realize the full therapeutic potential of NO. [8] NO donor and the delivery system are the primary concerns in design the NO delivery system. Many researchers over the past two decades have focused on using N-diazeniumdiolates (NONOates) and S-nitrosothiols (SNOs) as leading candidates for controlled NO delivery, due to their relatively high stability, their ability to spontaneously release NO under physiological conditions (e.g., no enzyme required) in a predictable manner, and their higher bioavailability in vivo.…”

“…[12] In an attempt to deliver NO in a targeted and controlled means, stimulus-responsive NO release systems have attracted considerable attention, because they can realize smart release typically featuring spatial, temporal, or dose-controlled delivery, and enabling NO-mediated treatment. [5b] As for triggers of stimulus-responsive NO release systems, some endogenous triggers, [13] for example, enzyme, [14] thiyl radical, [15] and copper ion, [8] were initially explored. However, these endogenous triggers were not specific in tumors but universal in diverse organs, resulting in failure of on-demand release.…”

“…Therefore, special attentions and careful considerations are needed in designing NO delivery system that can realize the full therapeutic potential of NO. [ 8 ]…”

“…As for triggers of stimulus‐responsive NO release systems, some endogenous triggers, [ 13 ] for example, enzyme, [ 14 ] thiyl radical, [ 15 ] and copper ion, [ 8 ] were initially explored. However, these endogenous triggers were not specific in tumors but universal in diverse organs, resulting in failure of on‐demand release.…”