Description du projet
De nouveaux médicaments à base de métaux et de peptides pour la thérapie photodynamique du cancer
La thérapie photodynamique du cancer utilise la lumière pour activer des médicaments autrement inertes. Elle minimise les problèmes de toxicité, car elle veille à ce que les médicaments tuent les cellules tumorales et non les cellules normales. Toutefois, les problèmes de pénétration de la lumière, l’hypoxie tumorale et la faible absorption des médicaments par les cellules cancéreuses compromettent la réussite de la thérapie photodynamique. Financé par le programme Actions Marie Skłodowska-Curie, le projet pepRu4PACT développera des médicaments à base de métaux qui sont activés par la lumière rouge ou proche infrarouge. Ces composés de ruthénium fonctionnent dans des conditions de faible teneur en oxygène et seront associés à des peptides antitumoraux afin d’améliorer l’absorption du promédicament par les cellules tumorales.
Objectif
One of the most severe limitations of current anticancer chemotherapy are the serious side effects caused by toxic drugs affecting not only tumors but also healthy organs. Local activation of drugs by light irradiation of the tumor is a promising approach to control where the toxicity is delivered. Metal complexes are well suited for photoactivated chemotherapy, but their activation wavelength is often too low to afford high tissue penetration of light; also, their ability to enter cancer cells is often controlled by lipophilicity tuning, which is unselective; finally, their phototoxicity often relies on oxygen-dependent mechanisms, while many tumor tissues show low dioxygen concentrations.
The aim of this proposal is to develop new metallodrugs that are activated by red or near-infrared light, enter cells by controlled mechanisms, and deliver strong phototoxicity to cancer cells also under low oxygen conditions. The design is based on connecting multiple Ru(II) metal complexes to a biologically active antitumoral peptide. The ruthenium complexes will have a tuned coordination environment to allow red/near-IR light activation; meanwhile, the peptides will rely on methionine residues to coordinate ruthenium, and allow controlled cellular uptake of the prodrug into cancer cells. Both components will cage each other in the dark, thus affording low toxicity; while light-induced cleavage of the ruthenium-thioether bonds will release two bioactive components, which will kill cancer cells.
The novelty of this proposal is to combine metal-based photoactivated chemotherapy with therapeutic peptides to enhance phototoxicity by creating synergies between both photoproducts. By combining light activation, resulting in timely- and spatially-resolved toxicity release, and bioactive peptides, which will improve uptake in cancer cells, this project will deliver new fundamental knowledge on the interaction between peptides and metals, and between metallopeptides and cells.
Champ scientifique
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-AG-UN - HORIZON Unit GrantCoordinateur
2311 EZ Leiden
Pays-Bas