The serum protein binding of pharmacologically active gallium(III) compounds assessed by hyphenated CE-MS techniques.
Transition metal-based drugs exhibit high affinity to the soft donors of human serum proteins, especially of the high-abundance protein HSA and of transferrin (Tf), whereas Ga(III) salts are known to bind to Tf and other iron-containing metalloproteins, thereby interfering with the iron metabolism. Herein, the utilization of CE-MS methods for studying the binding behavior of a therapeutic gallium nitrate formulation and the anticancer drug candidate Tris(8-oxyquinolinato)gallium(III) to Tf and HSA under simulated physiological conditions is described. Both the Ga(III) salt and the complex were found to bind to Tf exclusively in the presence of carbonate, however, at different kinetics and to a different extent. Fe(III) induces the release of the Ga ions due to the higher affinity constant and also prevents the Ga(III) species from accessing the iron-binding pockets of Tf. In contrast, only low affinity to HSA was observed and even when present at ca. 20-fold excess, the majority of the Ga was attached to Tf.
Groessl
Michael
M
University of Vienna, Institute of Inorganic Chemistry, Vienna, Austria.
Bytzek
Anna
A
Hartinger
Christian G
CG
D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001667:Binding, Competitive; D002138:Calibration; D019075:Electrophoresis, Capillary / Q000379:methods*; D005708:Gallium / Q000097:blood* / Q000493:pharmacokinetics; D005709:Gallium Isotopes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D013058:Mass Spectrometry / Q000379:methods*; D008954:Models, Biological; D009942:Organometallic Compounds / Q000097:blood* / Q000493:pharmacokinetics; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D014168:Transferrin / Q000378:metabolism*
D000970:Antineoplastic Agents; D005709:Gallium Isotopes; D009942:Organometallic Compounds; D012709:Serum Albumin; D014168:Transferrin; C408502:tris(8-quinolinolato)gallium (III); D015125:Oxyquinoline; D005708:Gallium; D007501:Iron; C027235:gallium nitrate