Pharmaceutical formulation affects titanocene transferrin interactions.

Since the discovery of the anticancer activity of titanocene dichloride (TDC), many derivatives have been developed and evaluated. MKT4, a soluble, water-stable formulation of TDC, was used for both Phase I and Phase II human clinical trials. This formulation is investigated here by using (1)H and (13)C NMR, FT-ICR mass spectrometry, and UV/vis-detected pH-dependent speciation. DFT calculations are also utilized to assess the likelihood of proposed species. Human serum transferrin has been identified as a potential vehicle for the Ti anticancer drugs; these studies examine whether and how formulation of TDC as MKT4 may influence its interactions, both thermodynamic and kinetic, with human serum transferrin by using UV/vis absorption and fluorescence quenching. MKT4 binds differently than TDC to transferrin, showing different kinetics of binding as well as a different molar absorptivity of binding (7500 M(-1) cm(-1) per site). Malate, used in the buffer for MKT4 administration, acts as a synergistic anion for Ti binding, shifting the tyrosine to Ti charge transfer energy and decreasing the molar absorptivity to 5000 M(-1) cm(-1) per site. These differences may have had consequences after the change from TDC to MKT4 in human clinical trials.