Light, ruthenium, and liposomes in chemotherapy

Scheme 1. Two pathways for the activation of ruthenium complexes. Above shown the spontaneous hydrolysis and below the pro-drug
Scheme 1. Two pathways for the activation of ruthenium complexes. Above shown the spontaneous hydrolysis and below the pro-drug
Project supervisor: 
Sylvestre Bonnet
Researcher: 
Vincent van Rixel

In the developed world cancer has become the number one cause of death. A lot of research therefore focuses on developing and improving anti-cancer treatment in the areas of tumor localization, irradiation, surgery, and chemotherapy. The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. These treatments not only targets cancer cells, but also healthy cells leading to nephrotoxicity (damage to the kidneys), neuromuscular complications, ototoxicity (damage to the ear), and gastrointestinal discomforts.1,2 Furthermore, some cancers may show platinum-resistance, thus other and preferably better alternatives are needed.

At MCBIM we develop ruthenium-polypyridyl complexes that can interact with biomolecules with a view to use them for chemotherapy.3 However, like platinum based anti-cancer agents these complexes may lack selectivity, too. By adding a protective group on the metal we prevent the complex to interact with biomolecules, while recovering their binding properties by local activation.4 Light irradiation of the tumor leads to removal of the protecting group, which activates the toxicity of the complex. Ultimately cytotoxicity is limited to irradiated cancer cells, which we hope will decrease side effects significantly.

Drug efficiency and effectiveness are further increased by supporting the ruthenium complexes onto liposomes. Some liposomes have the advantage of longer residence time in the body compared to small molecules, and selective uptake by tumors. This drug-delivery strategy is already used for delivering chemotherapeutics such as doxorubicine or cisplatin, for which liposomes show more selective action than the “naked” anticancer compound.5 By combining the strengths of ruthenium-based drugs, liposomes, and light-activation, we hope to achieve efficient and selective anticancer treatments with less side effects and higher efficacy for future cancer patients.

References: 

1. E. Antonarakis, A. Emadi Cancer Chemotherapy and Pharmacology 2010, 66, 1.
2. G. Gasser, I. Ott, N. Metzler-Nolte Journal of Medicinal Chemistry 2010, 54, 3.
3. O. Novakova, J. Kasparkova, O. Vrana, P.M. van Vliet, J. Reedijk, V. Brabec Biochemistry 1995, 34, 12369.
4. R.E. Goldbach, I. Rodriguez-Garcia, J.H. van Lenthe, M.A. Siegler, S. Bonnet Chemistry: A European Journal 2011, 17, 9924.
5. J.H. Park, G. von Maltzahn, M.J. Xu, V. Fogal, V.R. Kotamraju, E. Ruoslahti, S.N. Bhatia, M.J. Sailor Proceedings of the National Academy of Sciences of the United States of America 2010, 107, 981.

20/05/2014