Ti(IV) Binds to Human Serum Transferrin More Tightly Than Does Fe(III)

Abstract

The binding of titanium(IV) to human serum transferrin in 50 mM Tris with 20 mM bicarbonate and 10 mM citrate at pH 7.4 was studied by UV/vis kinetics and by isothermal titration calorimetry. Ti(IV) citrate, [Ti(C6H4O7)3]8-, employed in this study was previously characterized and delivers the metal to transferrin rapidly, allowing the quantification of the intrinsic binding constants for Ti(IV) to the C- and N-sites of transferrin. The results after correcting for blood plasma conditions (pH 7.4, [HCO3-] = 27 mM) reveal that Ti(IV) binds with greater affinity (log K = 26.8 and 25.7) than Fe(III) (log K = 22.5 and 21.4) to transferrin, a finding not previously observed for other examined metal ions. The strength of metal binding to transferrin correlates with the Lewis acidity of the metal. Ti(IV) is more Lewis acidic than Fe(III) and is nearly the same size. The study also reveals that Ti(IV) binds more tightly to one site than the other, and this difference is due to both entropic and enthalpic contributions. The study has implications for the role of transferrin in the anticancer activity of Ti(IV) drugs and the serum binding of Ti(IV) ions released from implants or imaging reagents.

Cytotoxicity of a Ti(IV) compound is independent of serum proteins

“…Both titanocene dichloride and Ti(IV) citrate rapidly deliver Ti(IV) to Tf (6, 9). In the case of Ti(IV) citrate, even in the presence of millimolar concentrations of free citrate, the exchange rate of Ti (IV) transfer to micromolar amounts of Tf is fast (9). We have already established that Ti 2 -Tf does not exhibit any cytotoxicity.…”

“…Evidence in support of this hypothesis is that Tf (which possesses two identical metal-binding sites) is only 39% Fe(III)-saturated (7) and can thus bind and transport other metal ions, typically hard metal ions (8). Ti(IV) has been shown to bind with very high affinity to Tf (9, 10), even higher than Fe(III) (9). In vivo studies have shown Ti(IV) to be endogenously bound to Tf (11).…”

Synthesis, Characterization, Cytotoxicity, and Hydrolytic Behavior of C2‐ and C1‐Symmetrical TiIV Complexes of Tetradentate Diamine Bis(Phenolato) Ligands: A New Class of Antitumor Agents

“…[26][27][28][29][30][31] This protein leads to complete ligand stripping from the Ti IV core, and apparently allows somewhat selective cell penetration through the transferring receptors located more abundantly on tumor cell surfaces. Nevertheless, early loss of the most inert ligands abolishes their potential influence on the interaction with the biological target, and, thus, questions the contribution and influence of the particular ligand on the cytotoxic activity.…”

The serum protein binding of pharmacologically active gallium(III) compounds assessed by hyphenated CE‐MS techniques

“…The binding to transferrin (Tf) is believed to play an important role in the mode of action of gallium salts as the binding constant is similar to Fe(III). Ga ions can bind to the two metal sites of Tf with binding constants log K 1 5 20.3 and log K 2 5 19.3, whereas Fe 31 -Tf-binding constants are slightly higher at log K 1 5 22.8 and log K 2 5 21.5 [15,20]. Gallium salts exhibit activity in malignant lymphomas and bladder cancer, and modest therapeutic potential in prostate, cervix and ovarian cancer in clinical trials [14,16,[21][22][23][24][25][26][27][28][29][30].…”