Delivery of therapeutic carbon monoxide by gas-entrapping materials

Abstract

Carbon monoxide (CO) has long been considered a toxic gas but is now a recognized bioactive gasotransmitter with potent immunomodulatory effects. Although inhaled CO is currently under investigation for use in patients with lung disease, this mode of administration can present clinical challenges. The capacity to deliver CO directly and safely to the gastrointestinal (GI) tract could transform the management of diseases affecting the GI mucosa such as inflammatory bowel disease or radiation injury. To address this unmet need, inspired by molecular gastronomy techniques, we have developed a family of gas-entrapping materials (GEMs) for delivery of CO to the GI tract. We show highly tunable and potent delivery of CO, achieving clinically relevant CO concentrations in vivo in rodent and swine models. To support the potential range of applications of foam GEMs, we evaluated the system in three distinct disease models. We show that a GEM containing CO dose-dependently reduced acetaminophen-induced hepatocellular injury, dampened colitis-associated inflammation and oxidative tissue injury, and mitigated radiation-induced gut epithelial damage in rodents. Collectively, foam GEMs have potential paradigm-shifting implications for the safe therapeutic use of CO across a range of indications.

De Novo Construction of Fluorophores via CO Insertion-Initiated Lactamization: A Chemical Strategy toward Highly Sensitive and Highly Selective Turn-On Fluorescent Probes for Carbon Monoxide

“…The prospect of developing CO into a therapeutic agent for colitis, sickle cell disease, and acute kidney injury, among others, , is supported by the corresponding animal model studies. Extensive efforts have been made in recent years in evaluating inhaled CO gas in clinical trials, , developing non-gaseous CO delivery approaches, including liquid and foam formulations, metal-based CO-releasing molecules (CORMs), ,, and organic light-activated CORMs, − organic prodrugs, ,− and their formulations . A unique challenge to studying the dose–response relationship of CO is the lack of facile methods for the sensitive and selective determination of its concentration in the blood and various tissues. − Along this line, there is still much to be desired from existing methods.…”

“…CO exerts anti-inflammatory and cyto- and organ-protective effects. ,− For example, it offers protection in lipopolysaccharide-induced inflammation, ischemia–reperfusion injuries, , and chemically , and rhabdomyolysis -induced organ injuries. The prospect of developing CO into a therapeutic agent for colitis, sickle cell disease, and acute kidney injury, among others, , is supported by the corresponding animal model studies. Extensive efforts have been made in recent years in evaluating inhaled CO gas in clinical trials, , developing non-gaseous CO delivery approaches, including liquid and foam formulations, metal-based CO-releasing molecules (CORMs), ,, and organic light-activated CORMs, − organic prodrugs, ,− and their formulations .…”

Oral Use of Therapeutic Carbon Monoxide for Anyone, Anywhere, and Anytime

“…However, the tunability of the CO load and dosing seems to be unclear . Byrne at al . describe CO delivery by gas entrapping materials.…”

Structural Insights into Microbial One-Carbon Metabolic Enzymes Ni–Fe–S-Dependent Carbon Monoxide Dehydrogenases and Acetyl-CoA Synthases

“…9 Although CO is toxic at high concentrations, CO plays useful roles in host−gut microbiome communication and is being explored as a therapeutic for inflammatory disorders. 10 To prevent the toxic effects of CO, it is hypothesized that CODH acts as CO sink in the gastrointestinal tract to maintain proper CO balance. 11 Acetogens use CODHs as part of the Wood−Ljungdahl pathway of reductive acetogenesis (CO 2 to acetate).…”

“…Collectively, CODH-catalyzed CO oxidation eliminates approximately 10 8 tons of CO from our environment annually (Scheme ). Although CO is toxic at high concentrations, CO plays useful roles in host–gut microbiome communication and is being explored as a therapeutic for inflammatory disorders . To prevent the toxic effects of CO, it is hypothesized that CODH acts as CO sink in the gastrointestinal tract to maintain proper CO balance …”