Speciation of the Potential Antitumor Agent Vanadocene Dichloride in the Blood Plasma and Model Systems

摘要

The speciation of the potential antitumor agent vanadocene dichloride ([Cp2VCl2], abbreviated with VDC) in the blood plasma was studied by instrumental (EPR, ESI-MS, MS-MS, and electronic absorption spectroscopy) and computational (DFT) methods. The behavior of VDC at pH 7.4 in aqueous solution, the interaction with the most important bioligands of the plasma (oxalate, carbonate, phosphate, lactate, citrate, histidine, and glycine among those with low molecular mass and transferrin and albumin between the proteins) was evaluated. The results suggest that [Cp2VCl2] transforms at physiological pH to [Cp2V(OH)(2)] and that only oxalate, carbonate, phosphate, and lactate are able to displace the two OH- ions to yield [Cp2V(ox)], [Cp2V(CO3)], [Cp2V(lactH(-1))], and [Cp2V-(HPO4)]. The formation of the adducts with oxalate, carbonate, lactate, and hydrogen phosphate was confirmed also by ESI-MS and MS-MS spectra. The stability order is [Cp2V(ox)] [Cp2V(CO3)] > [Cp2V-(lactH(-1))] > [Cp2V(HPO4)]. No interaction between VDC and plasma proteins was detected under our experimental conditions. Several model systems containing the bioligands (bL) in the same relative ratio as in the blood samples were also examined. Finally, the speciation of VDC in the plasma was studied. The results obtained show that the model systems behave as the blood plasma and indicate that when V concentration is low (10 mu M) VDC is transported in the bloodstream as [Cp2V(ox)]; when V concentration is high (100 mu M) oxalate binds only 9.2 mu M of [Cp2V](2+), whereas the remaining part distributes between [Cp2V(CO3)] (main species) and [Cp2V(lactH(-1))] (minor species); and when V concentration is in the range 10-100 mu M [Cp2V](2+) distributes between [Cp2V(ox)] and [Cp2V(CO3)].