Project Portugal 2030

Summary

Research over the last 20 years on small molecule carriers of carbon monoxide has almost invariably involved metal carbonyl complexes (MCC). The use of light as the trigger to unload CO opens the possibility of a spatial and temporal control of CO delivery to the biological target. However, hundreds of compounds from the vast library of known MCC have not been considered as photoactivatable CO-releasing molecules (CORMs) since they only undergo photodecarbonylation upon exposure to high energy UV light, which is cytotoxic and poorly suited for tissue penetration. Research over recent years has therefore attempted to shift the light activation wavelength from the UV region to the visible. This has been achieved quite successfully by design of organic co-ligands for MCC. However, the effective modulation of the photophysical properties often requires structurally complex conjugated and aromatic ligands. Moreover, it is extremely challenging to use this strategy to shift the activation window toward the near-infrared (NIR) range (700-1000 nm), which is known as the therapeutic window due to the low tissue absorption, low scattering, and low autofluorescence. It would therefore be of great value to develop a universal strategy for using NIR light to activate CORM prodrugs based on simple MCC, including even homoleptic carbonyls that contain only CO ligands, that require UV light for photodecarbonylation. This project proposes to tackle this problem by conjugating drug carriers (containing the MCC) with lanthanide-doped nanoparticles (NPs) that can effect NIR-to-visible or UV upconversion. To date, this strategy has only been reported for two visible light-activated CORMs and therefore its true potential has not been realized. To achieve the goal of NIR-responsive nanocomposites (NCs) for the storage and delivery of CO, and to explore a potential biological application, we propose the following specific objectives: 1) To review the existing literature on CORMs to draw up a list of target MCC, ranging from simple homoleptic carbonyls to more complex heteroleptic compounds, to serve as model complexes and for incorporation into metal-organic frameworks (MOFs). 2) Lab-scale synthesis and characterization of the complexes that are more susceptible to release of CO upon UV or visible light irradiation. A desirable property of the synthesized complexes is the solubility and stability in water. 3) Explore the CO-release behaviors of the compounds, screening different media and release mechanisms. 4) Use at least two different detection methods for the quantification of CO released from CORMs, namely gas chromatography and the myoglobin assay. 5) Incorporation of metal carbonyls into MOFs by 3 different approaches. Characterize the prepared materials in the solid state by multiple techniques. 6) Synthesis and characterization of upconversion (UC) NCs for the near-infrared photo-controlled release of CO. The main general strategy will be NCs based on UC NPs and MOF supports containing photoactivatable CO-releasing centers. 7) Explore the CO-release behaviors of synthesized CORMAs, compare with “free” CORMs, and characterize recovered CORMAs to gauge structural alterations, nature of decarbonylation fragments, leaching phenomena. 8) Validate potential antibacterial activity of the CO-releasing compounds and evaluate the possible side effects on human cells after treatment with the same compounds.