Metallacarboranes on the Road to Anticancer Therapies: Cellular Uptake, DNA Interaction, and Biological Evaluation of Cobaltabisdicarbollide [COSAN]-

Authors:   I. Fuentes, T. García-Mendiola, S. Sato, M. Pita, H. Nakamura, E. Lorenzo, F. Teixidor, F. Marques and C. Viñas
Journal: Chemistry European Journal
https://doi.org/10.1002/chem.201803178
Abstract: After uptake by U87 MG and A375 cancer cells, cobaltabisdicarbollide [COSAN]? distributes between membrane and nucleus and presents no relevant cytotoxicity against both cell lines even for long incubation times. The cytotoxicity of Na[COSAN] was also tested towards one normal cell line, the V79 fibroblasts, in order to ascertain the noncytotoxic profile of the compound. As the cell’s nucleus contains DNA, the interaction between [COSAN]? and double-stranded calf thymus DNA (CT-dsDNA) has been investigated. There is a strong interaction between both molecules forming a nanohybrid CT-dsDNA-[COSAN] biomaterial, which was fully characterized. Moreover, Na[COSAN] shows characteristic redox peaks ascribed to the oxidation/reduction of Co3+/2+ at a formal potential of ?1.444 V and it can be accumulated at a surface-immobilized DNA layer of glassy carbon electrodes. The equilibrium surface-binding constants (Kox/Kred), which confirm that [COSAN]? interacts with DNA by an intercalative or electrostatic mode, depending on the ionic strength of the solution, were estimated. In addition, high binding affinity of Na[COSAN] to proteins was observed by 11B{1H} NMR and confirmed in vivo. Finally, biodistribution studies of [COSAN]? in normal mice were run. After administration, Na[COSAN] was distributed into many organs but mainly accumulated in the reticuloendothelial system (RES), including liver and spleen. After 1 h, the formation of aggregates by plasma protein interaction plays a role in the biodistribution profile; the aggregates accumulate mostly in the lungs. Na[COSAN], which displays low toxicity and high uptake by relevant cancer cells accumulating boron within the nucleus, could act as a suitable compound for further developments as boron neutron capture therapy (BNCT) agents.