Light-activatable ruthenium-based anticancer prodrugs
Date du début: 1 juin 2013,
Date de fin: 31 mai 2018
Chemotherapy is, after surgery, the second most efficient therapy against cancer. However, it has many side effects for cancer patients because anticancer drugs kill cancer cells but also healthy ones. My project aims at synthesizing new metal-containing compounds that 1) are poorly toxic in the dark; 2) can be attached via a light-sensitive bond to liposomes that will carry them into cancer cells; and 3) detach from their carriers and become toxic upon light irradiation, thus killing cancer cells.These new compounds contain ruthenium, a metal combining photochemical and anticancer properties. I will replace the weakly bound chloride ligands of known cytotoxic ruthenium compounds by strongly bound sulfur ligands. By doing so, the DNA- and protein-binding ability of the ruthenium compounds will be lowered, which will lower their toxicity in the dark. Thioether-lipid conjugates will be used to attach the ruthenium prodrugs to liposomes carriers that are well taken up by cancer cells.Techniques to irradiate tumors in vivo are nowadays available in the clinics. By shining light onto the ruthenium-enriched cancer cells photochemical cleavage of the Ru-S bond will take place, thus detaching the metal complex from its carrier and allowing it for binding to biological molecules. Thus, the ruthenium prodrug will be transformed inside cancer cells into a highly toxic molecule that will kill the cells. I will study mononuclear compounds and molecules containing several ruthenium centres; visible light activation and near infrared light activation. The final aim is to obtain ruthenium-functionalized liposomes that are poorly toxic in the dark, preferentially go into cancer cells, and become toxic at the place of irradiation, using light that penetrates well into biological tissues.Because of this unique combination of properties my new light-activatable ruthenium prodrugs will ultimately lead to selective anticancer treatment showing low side effects for cancer patients.
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