Projektbeschreibung
Neue Arzneimittel auf Metallpeptid-Basis zur photodynamischen Krebsbehandlung
Die photodynamische Krebstherapie nutzt Licht, um Arzneimittel zu aktivieren, die ohne dieses Licht inaktiv bleiben. Toxizitätsbedingte Probleme werden so minimiert, da die Arzneimittel durch diese Technik nur den Tumor, nicht aber normale Zellen abtöten. Die photodynamische Therapie ist allerdings auch mit gewissen Problematiken bei der Lichtpenetration sowie mit Tumorhypoxie und einer schlechten Wirkstoffaufnahme in den Krebszellen verbunden, was ihrer erfolgreichen Anwendung im Wege steht. Das im Rahmen der Marie-Skłodowska-Curie-Maßnahmen finanzierte Projekt pepRu4PACT wird Arzneimittel auf Metallbasis entwickeln, die durch Rotlicht oder Nah-Infrarotlicht aktiviert werden. Diese Ruthenium-Verbindungen wirken unter sauerstoffarmen Bedingungen und werden an antitumorale Peptide gekoppelt, um die Aufnahme des Pro-Arzneimittels in den Tumorzellen zu verstärken.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
HORIZON-AG-UN - HORIZON Unit GrantKoordinator
2311 EZ Leiden
Niederlande