Design and Synthesis of Macromolecular Scaffolds for Carbon Monoxide Delivery in Biological Systems

CO has been recognised as a signalling molecule in mammalian organisms and is involved in regulating physiological and pathophysiological pathways. CO has also been demonstrated to have potent anti-inflammatory,... [ view full abstract ]

CO has been recognised as a signalling molecule in mammalian organisms and is involved in regulating physiological and pathophysiological pathways. CO has also been demonstrated to have potent anti-inflammatory, anti-proliferative and anti-apoptotic effects. The significant therapeutic effects of controlled CO inhalation have been proven in animal models of disease with the anti-inflammatory activity of CO studied in phase II clinical trials. However, the therapeutic benefits of CO gas administration have remained questionable as a result of its systemic toxicity at high concentrations and difficulties in storing and delivering gaseous CO to the target tissue in a controlled manner.
To overcome these limitations, chemists have developed molecules capable of releasing carbon monoxide (CORMs) as pharmaceutical agents for safer, more convenient and controlled CO release. Among CORMs, the commercial CORM-2 and CORM-3 are one of the most common CO-releasing molecules used in biological studies. These compounds exert significant biological properties including anti-inflammatory and antimicrobial activities. However, the clinical use of these compounds as therapeutic agents is limited owing to their short CO-releasing half-life and poor solubility in aqueous solutions. These drawbacks can be addressed by using macromolecular scaffolds as CO carries. Macromolecular carriers, such as polymeric nanoparticles appear to be an ideal vehicle for the transport of drugs because their sizes can be easily tuned, permitting the passive accumulation in a tumor tissue via the enhanced permeability and retention (EPR) effect. Additionally, macromolecular carriers offer a high CO-loading capacity due to the attachment of several CO per macromolecule, resulting in a significant increase in the CO concentration. Furthermore, nanocarriers not only enhance the therapeutic efficacy, but they also reduce the systemic toxicity of drugs, which results in a reduction in side effects. Inspired both by the excellent biological activities of CORM-2/CORM-3 and many advantages of macromolecular materials offering, we aimed to construct novel multifunctional macromolecular systems that possess the features allowing the controlled and selectively delivery of CO. This work opens up new strategy for the development of CO-releasing scaffolds in biological applications.