Descripción del proyecto
Nuevos fármacos a base de metalopéptidos para la terapia fotodinámica del cáncer
La terapia fotodinámica del cáncer utiliza la luz para activar fármacos que, de otro modo, permanecerían inertes. Este proceso minimiza los problemas de toxicidad, ya que garantiza que los fármacos eliminen las células tumorales y no las células normales. Sin embargo, los problemas de penetración de la luz, la hipoxia tumoral y la escasa absorción del fármaco por parte de las células cancerosas impiden que la terapia fotodinámica tenga éxito. El equipo del proyecto pepRu4PACT, financiado por las Acciones Marie Skłodowska-Curie, desarrollará fármacos a base de metales que se activan mediante luz roja o infrarroja cercana. Estos compuestos de rutenio funcionan en condiciones de hipoxia y se acoplarán a péptidos antineoplásicos para potenciar la absorción del profármaco por parte de las células tumorales.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-AG-UN - HORIZON Unit GrantCoordinador
2311 EZ Leiden
Países Bajos