Descrizione del progetto
Nuovi farmaci metallo-peptidici per la terapia fotodinamica del cancro
La terapia fotodinamica del cancro utilizza la luce per attivare farmaci altrimenti inerti. Questo riduce al minimo i problemi di tossicità, in quanto garantisce che i farmaci uccidano il tumore e non le cellule normali. Tuttavia, i problemi di penetrazione della luce, l’ipossia tumorale e lo scarso assorbimento del farmaco da parte delle cellule tumorali ostacolano il successo della terapia fotodinamica. Il progetto pepRu4PACT, finanziato dal programma di azioni Marie Skłodowska-Curie, svilupperà farmaci a base di metalli che si attivano con la luce rossa o vicina all’infrarosso. Questi composti di rutenio funzionano in condizioni di basso ossigeno e saranno accoppiati a peptidi antitumorali per migliorare l’assorbimento del profarmaco da parte delle cellule tumorali.
Obiettivo
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.
Campo scientifico
Programma(i)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Meccanismo di finanziamento
HORIZON-AG-UN - HORIZON Unit GrantCoordinatore
2311 EZ Leiden
Paesi Bassi