title: Pharmaceutical formulation affects titanocene transferrin interactions.
abstract: 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.
authors.affiliation: Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Buettner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Snoeberger
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.forename: Ann M
authors.initials: AM
authors.lastname: Valentine
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D005079:Excipients / Q000378:metabolism*; D006801:Humans; D009942:Organometallic Compounds / Q000378:metabolism*; D011485:Protein Binding; D013816:Thermodynamics; D014168:Transferrin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005079:Excipients; D009942:Organometallic Compounds; D014168:Transferrin; C020528:titanocene dichloride