ESI-MS And CE-ICP-MS Probing Of Anticancer Metallodrug KP1019 Interactions With Cytosol Components

Due to the great separation potential of capillary electrophoresis(CE)and the metal-specificity of inductively coupled plasma mass spectrometry(ICP-MS),this coupled system is used to investigate the mechanism of actions of indazolium[trans-tetrachlorobis(1H-indazole)ruthenate(III)](KP1019),a promising anticancer metallodrug,that successfully finished phase I of clinical studies.Kinetics of binding reactions of KPP1019 towards holo-transferrin(hTf)were studied in the first stage of this work,proving that the formation of KP1019-holo-transferrin adduct could be accomplished within 2 h of incubation at the simulated physiological extracellular conditions.Binding constant rate for adduct KP1019-hTf(2:1)was acquired with the aid of equation(1):k = 0.1011 ± 0.0081 min-1(n = 9).Throughout the experiments performed by CE-ICP-MS,it was clearly observed that iron species and ruthenium species could be released from KP1019-holo-transferrin adduct at simulated physiological intracellular conditions in the presence of individual reductant or all of them.In order to further study the activation-by-reduction hypothesis,the experiments with use of ESI-MS were carried out.The obtained results proved that the redox conversion of RuIII to RuII can occur in the presence of GSH or ascorbic acid under simulated physiological intracellular conditions,generating Ru11 species which is generally considered to be more active towards biomolecules.