Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - LIGHT-CORM-CAT (Development of novel Near-infrared Light-triggered CORMs for Cancer Treatment)

SUMMARY DESCRIPTION OF THE PROJECT OBJECTIVES

Carbon monoxide (CO) plays an important role in the regulation of the stress response and in cell adaption to injury. Pre-clinical trials applying this molecule as a therapeutic agent have already shown that it has useful therapeutic effects, e.g. anti-inflammatory, vasodilatory and anti-microbial properties, when administered in appropriate and controlled doses.
Carbon monoxide-releasing molecules (CORMs) represent a promising prodrug approach for the safe storage and controlled release of CO. Considerable research has been directed towards the development of light-activated CORMs (“photoCORMs”), which release CO only upon exposure to electromagnetic radiation. A major benefit of this approach is that the intensity, shape, duration and direction of a light beam can be readily manipulated, enabling CO release to be controlled with extreme accuracy. Nowadays, the challenge lies in tuning photoCORMs that can be activated with low energy wavelengths, i.e. preferably visible or near-infrared light rather than UV radiation, since the latter is damaging to tissues and has low skin penetration depth. Upconverting nanoparticles (UCNPs) are powerful materials that convert near infrared light into visible light. Therefore, the proposed approach employs UCNPs decorated with ruthenium-based, visible light-activated CORMs and a cell-penetrating peptide to enhance the cell uptake. It will be the first study of its kind to probe in detail the uptake, trafficking and light-triggered activation of NIR photo-CORMs in cells using a suite of high-resolution spectroscopic techniques.
This combination of new methodology and novel CORMs will not only provide a new non-invasive technology to elucidate the interaction of CO and CORMs with living organisms, but also deliver agents that can be used to simultaneously monitor and treat diseases in a specific and safe manner with optical-based techniques.

A DESCRIPTION OF THE WORK PERFORMED SINCE THE BEGINNING OF THE PROJECT

Since the beginning of the project, the Research Fellow has worked on the (i) synthesis of ruthenium(II) carbonyl complexes (Ru(II) CORMs) bearing electron-donating and/or electron-withdrawing groups, (ii) kinetic studies on the rate of CO release in different solvent systems upon illumination at 350 nm by using different spectroscopic techniques, (iii) attachment of UCNPs to the Ru(II) CORMs, (iv) synthesis of a cell-penetrating peptide, and (v) in vitro studies of Ru(II) CORMs to evaluate the uptake and cell viability before and after light-activation (see attachment, work packages).

A DESCRIPTION OF THE MAIN RESULTS ACHIEVED SO FAR

The Research Fellow has worked intensively on the elucidation of CO loss from ruthenium(II) carbonyl complexes upon illumination at 350 nm in different solvent systems (acetonitrile and 1% DMSO (v/v) in water). This has culminated in a recent publication in Inorganic Chemistry [1]. Three ruthenium(II) bipyridine carbonyl complexes were synthesised with auxiliary groups with electron-donating or electron-withdrawing properties. The photolysis and the release of CO from the complexes was monitored by UV-Vis absorbance spectroscopy and evaluated by multivariate curve resolution-alternating least squares (MCR-ALS) analysis. The number of reaction components was determined and quantitative kinetic information extracted. The results point to a serial mechanism and thus a successive loss of CO. Release of the first CO molecule is very fast, with the free vacancy immediately filled by a solvent molecule. The release of the second CO molecule was considerably slower, and electron-withdrawing carboxyl groups were found to reduce the rate of decarbonylation. This study also demonstrated that the release of CO in an aqueous solution is less distinguished and the rate constant for this process is lower than in a coordinating organic solvents (e.g. acetonitrile). These results highlight that using organic solvents may not be directly translatable to the biological/medicinal realm.
The multivariate curve resolution-alternating least squares (MCR-ALS) analysis, and associated kinetic fitting, is novel for this kind of study. The comprehensive data obtained provide a strong impetus for employing MCR-ALS analysis to study the mechanism of prodrugs, e.g. photoCORMs, in particular because it is not limited to one spectroscopic technique.

Reference
[1] M. Kubeil, R. R. Vernooij, C. Kubeil, B. Wood, B. Graham, H. Stephan, L. Spiccia: Studies of carbon monoxide release from ruthenium(II) bipyridine carbonyl complexes upon UV light exposure, Inorg. Chem., 2017, 56, 5941-5952.

THE EXPECTED FINAL RESULTS AND THEIR POTENTIAL IMPACT AND USE

The project is one of the first studies of its kind to probe in detail the uptake, trafficking and NIR light-triggered activation of photoCORMs in cells. The use of UCNPs for activation of photoCORMs is a promising concept, with the potential to greatly extend the scope of photodynamic therapy by enabling destruction of cancerous cells at greater tissue depths. The project will deliver important information about the photoCORM's mechanisms of action, biodistribution, degradation/elimination routes, and the kinetics of CO liberation and uptake by cells. This knowledge will be exploited in the development of new prodrug candidates.
A first milestone has been achieved, namely an improved understanding of the relation between CORM structure and CO release in aqueous solutions. The Research Fellow has implemented and applied chemometric data analysis (MCR-ALS) to elucidate the mechanism and kinetics of CO release from photoCORMs to understand their degradation behaviour. This is the first time MCR-ALS analysis and the associated kinetic fitting has been applied to CO-releasing molecules, and the methodology can potentially be extended to any other class of compounds, as well as the analysis of data acquired with other spectroscopic techniques. As such, the project is pioneering methods to gain insights into intermediates and products formed during the photolysis of photoCORMs. This knowledge will be exploited to develop efficiently more specific and effective molecule designs.

Related information

Reported by

HELMHOLTZ-ZENTRUM DRESDEN-ROSSENDORF EV
Germany

Subjects

Life Sciences
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