Issue 37, 2011

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 1H and 13C 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.

Graphical abstract: Pharmaceutical formulation affects titanocene transferrin interactions

Supplementary files

Article information

Article type
Paper
Submitted
30 Apr 2011
Accepted
10 Jun 2011
First published
16 Aug 2011

Dalton Trans., 2011,40, 9580-9588

Pharmaceutical formulation affects titanocene transferrin interactions

K. M. Buettner, R. C. Snoeberger III, V. S. Batista and A. M. Valentine, Dalton Trans., 2011, 40, 9580 DOI: 10.1039/C1DT10805K

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