Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.
CO is best known for its toxicity in carbon monoxide poisoning at high doses. However, CO is a gasotransmitter and supplemental low dosage of CO has been linked to therapeutic benefits. Pre-clinical research has focused on CO's anti-inflammatory activity with significant applications in cardiovascular disease, oncology, transplant surgery, and neuroprotection.
History
The simplest source of CO is from a combustion reaction via burning sources such as fossil fuels or fire wood. Sources releasing CO upon thermal decomposition or combustion are generally not considered CORMs.
Therapeutic interest in CO dates back to the study of factitious airs (hydrocarbonate) in the 1790s by Thomas Beddoes, James Watt, James Lind, Humphry Davy, Tiberius Cavallo and many others.
Nickel tetracarbonyl was the first carbonyl-complex used to achieve local delivery of CO and was the first CO delivery molecule suggested to have therapeutic potential in 1891. The acronym CORM was coined in 2002 which marks the first modern biomedical and pharmaceutical initiative. The enzymatic reaction of heme oxygenase inspired the development of synthetic CORMs.
The first synthetic CORMs were typically metal carbonyl complexes. A representative CORM that has been extensively characterized both from a biochemical and pharmacological view point is the ruthenium(II) complex Ru(glycinate)Cl(CO)3, commonly known as CORM-3. Therapeutic data pertaining to metallic CORMs are being reappraised to elucidate if observed effects are actually due to CO, or, if metal reactivity mediates physiological effects via thiol depletion, facilitating reduction, ion channel blockage, or redox catalysis. Despite questions pertaining to transition metals, pure CO gas and alternative non-metallic CO prodrugs and drug delivery devices have confirmed CO's therapeutic potential.
CORM classifications
Transition metal CORMs
The majority of therapeutically relevant CORMs are transition metal complexes primarily based on iron, molybdenum, ruthenium, manganese, cobalt, rhenium and others.
PhotoCORMs
The release of CO from carrier agents can be induced photochemically. These carriers are called photoCORMs and include both metal complexes and metal-free (organic) compounds of various structural motifs which could be regarded as a special type of photolabile protecting group.
ET-CORMs
Enzyme-triggered CORMs (ET-CORMs) have been developed to improve selective local delivery of CO. Some ET-CORM prodrugs are activated by esterase enzymes for site specific liberation of CO.
CO prodrugs
Organic CORMs are being developed to overcome reactivity and certain toxicity limitations of inorganic CORMs.
Methylene chloride was the first organic CORM orally administered based on previous reports of carboxyhemoglobin formation via metabolism. The second organic CORM, CORM-A1 (sodium boranocarbonate), was developed based on a 1960s report of CO release from potassium boranocarbonate.
In 2003, cyclic oxocarbons were suggested as a source for therapeutic CO including deltic acid, squaric acid, croconic acid, and rhodizonic acid and their salts.
Recent years have seen increasing interests in organic CO prodrugs because of the need to consider drug developability issues in developing CO-based therapeutics. These CO prodrugs have tunable release rate, triggered release, and the ability to release more than one payload from a single prodrug.
Enzyme hybrids
Based on the synergism of the heme oxygenase system and CO delivery, a new molecular hybrid-CORM (HYCO) class emerged consisting of a conjoined HO-1 inducer and CORM species. One such HYCO includes a dimethyl fumarate moiety which activates NRF2 to thereby induce HO-1, whilst the CORM moiety also liberates CO.
Carbon monoxide releasing materials
Carbon monoxide releasing materials (CORMAs) are essentially novel drug formulations and drug delivery platforms which have emerged to overcome the pharmaceutical limitations of most CORM species. An exemplary CORMA developed by Hubbell consists of a formulation of micelles prepared from triblock copolymers with a CORM entity, which is triggered for release via addition of cysteine. Other CO-releasing scaffolds include polymers, peptides, silica nanoparticles, nanodiamond, magnetic nanoparticles, nanofiber gel, metallodendrimers, and CORM-protein (macromolecule) conjugates.