title: Metallomics for drug development: serum protein binding and analysis of an anticancer tris(8-quinolinolato)gallium(III) drug using inductively coupled plasma mass spectrometry.
abstract: The application of an inductively coupled plasma mass spectrometry (ICP-MS) assay for quantifying in vitro binding of a gallium-based anticancer drug, tris(8-quinolinolato)gallium(III), to serum albumin and transferrin and in human serum is described. The distribution of the drug between the protein-rich and protein-free fractions was assessed via ICP-MS measurement of total gallium in ultrafiltrates. Comparative kinetic studies revealed that the drug exhibits a different reactivity toward individual proteins. While the maximum possible binding to albumin (~10%) occurs practically immediately, interaction with transferrin has a step-like character and the equilibrium state (with more than 50% binding) is reached for about 48 h. Drug transformation into the bound form in serum, also very fast, results in almost quantitative binding (~95%). The relative affinity of protein-drug binding was characterized in terms of the association constants ranging from 10(3) to 10(4)M(-1). In order to further promote clinical testing of the gallium drug, the ICP-MS method was applied for direct quantification of gallium in human serum spiked with the drug. The detection limit for gallium was found to be as low as 20 ng L(-1). The repeatability was better than 8% (as RSD) and the achieved recoveries were in the range 99-103%.
authors.affiliation: Division of Analytical Chemistry, Chemistry Department, Moscow State University, Moscow, Russia.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Ossipov
authors.forename: Lidia S
authors.initials: LS
authors.lastname: Foteeva
authors.forename: Irina F
authors.initials: IF
authors.lastname: Seregina
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Perevalov
authors.forename: Andrei R
authors.initials: AR
authors.lastname: Timerbaev
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Bolshov
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D009942:Organometallic Compounds; D012709:Serum Albumin; D014168:Transferrin; C408502:tris(8-quinolinolato)gallium (III); D015125:Oxyquinoline