Ruthenium-Peptid-Biokonjugate für photoaktivierte Chemotherapie
Anorganische Molekülchemie - Synthese, Charakterisierung
Biochemie
Zusammenfassung der Projektergebnisse
One of the most severe limitations of current anticancer chemotherapy is 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 work 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 ultimate design comprises multiple Ru(II) metal complexes coordinated to a biologically active antitumoral peptide. The ruthenium complexes have a tuned coordination environment to allow red/near-IR light activation; meanwhile, the peptides rely on methionine residues to coordinate ruthenium, and allow controlled cellular uptake of the prodrug into cancer cells. Both components cage each other in the dark, thus affording low toxicity; while light-induced cleavage of the ruthenium-thioether bonds release two bioactive components, which kill cancer cells. In order to achieve such goal, intermediate objectives had to be established before: (a) tuning the coordination sphere of Ru(II)-polypyridyl complexes bound to thioethers to achieve light activation in the red or near-IR spectral region; (b) coordinating multiple Ru(II) complexes to a single peptide through the thioether moieties of methionine residues; (c) exploiting the synergistic cytotoxic activity of both the Ru complexes and the peptide. In view of the shorter funding period than originally requested, in this report, objectives (a) and (b) could be achieved and are described in Project 1 and Project 2, leaving objective (c) for future research. Content of Project 1 is the design of a new family of thioether-ruthenium(II) polypyridyl complexes that can be activated by ligand photosubstitution using red or near infrared light irradiation. We used amide groups and extended π-conjugation to fine tune the excited state energies and shift light absorption towards the red region. We discuss the structure-activity relationship of these complexes and relate chemical formulae, photochemical properties, and biological activity in a range of human cancer cell lines. While within Project 2, it was possible to successfully coordinate multiple Ru(II) complexes to a single peptide through the thioether moieties of methionine residues. Different combinations of Ru(II) complexes and peptides were investigated. Steric hindrance dictates the number of Ru(II) complexes that it is possible to coordinate per peptide. Finally, all bioconjugates showed full dissociation of the Ru complexes from the peptides upon light irradiation. Future research will focus on implementing cytotoxic peptides for the coordination of multiple cytotoxic Ru(II) complexes, and gain great 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 approach will deliver new fundamental knowledge on the interaction between peptides and metals, and between metallopeptides and cells.
Projektbezogene Publikationen (Auswahl)
-
Triplet-triplet annihilation upconversion for calcium sensing. American Chemical Society (ACS).
Andreeva, Valeriia D.; Yang, Tingxiang; Regeni, Irene; Dietzek-Ivanšić, Benjamin & Bonnet, Sylvestre A.
