Application of capillary electrophoresis-inductively coupled plasma mass spectrometry to comparative studying of the reactivity of antitumor ruthenium(III) complexes differing in the nature of counter-ion toward human serum proteins

Abstract

Varying the counter-ion is a highly supportive practice in tackling the problem of poor water-solubility of metal complexes of pharmaceutical importance. As a matter of fact, the relevant structural modification may alter the metabolic pathways and possibly the mode of action of a drug. To prove that this does not take place for one of the lead anticancer metal-based developmental compounds, indazolium trans-[RuCl4(1H-indazole)2] (KP1019), its reactivity toward human serum proteins was assessed under simulated physiological conditions and compared to that of a much more soluble analogue, sodium trans-[RuCl4(1H-indazole)2] (KP1339). For such kinetic assaying, capillary electrophoresis (CE) interfaced online with inductively coupled plasma mass spectrometry (ICP-MS) to specifically monitor changes in the metal speciation following the formation of ruthenium-protein adducts was applied. The rate constants of interaction with albumin and transferrin were determined at pharmacologically fitting drug-to-protein ratios as on average 0.0319 ± 0.0021 min-1 and 0.0931 ± 0.0019 min-1 (KP1019) and 0.0316 ± 0.0018 min-1 and 0.0935 ± 0.0053 min-1 (KP1339), respectively. The results of this brief study showed that changing from organic to inorganic counter-ion at the stage of formulation could commonly be recommended for improving ruthenium-based drug solubility and bioavailability. © 2008 Elsevier B.V. All rights reserved.