title: Inductively coupled plasma mass spectrometry for metallodrug development: albumin binding and serum distribution of cytotoxic cis- and trans-isomeric platinum(II) complexes.
abstract: Binding to plasma proteins is one of the major metabolic pathways of metallodrugs. In the case of platinum-based anticancer drugs, it is the interaction with serum albumin that affects most strongly their in vivo behavior. Since both the configuration, i.e. cis-trans-isomerism, and the nature of leaving groups have an effect on the reactivity of Pt(II) coordination compounds toward biomolecules, a set of cis- and trans-configured complexes with halide leaving groups (Cl(-), Br(-), and I(-)) and 2-propanone oxime as carrier ligands was chosen for this study. Binding experiments were performed both with albumin and human serum and the Pt content in ultrafiltrates was quantified using inductively coupled plasma mass spectrometry. In order to shed light on the binding mechanism, the albumin binding constant (KHSA) and the octanol-water partition coefficient (P) were experimentally determined and relationships between log KHSA and log P were explored. The correlation was found significant only for cis-configured platinum complexes (R(2)=0.997 and standard deviation=0.02), indicating a certain contribution of the nonspecific binding which is largely dominated by the lipophilicity of compounds. In contrast, for trans-complexes a specific molecular recognition element plays a significant role. The participation of albumin in drug distribution in blood serum was assessed using an equilibrium distribution model and by comparing the percentage binding in the albumin and serum-protein fractions. Irrespective of the compound polarity, albumin contributes from 85 to 100% to the overall binding in serum.
authors.affiliation: Division of Analytical Chemistry, Chemistry Department, Moscow State University, Leninskie Gory 1, 119992 Moscow, Russia.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Ossipov
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Scaffidi-Domianello
authors.affiliation: Division of Analytical Chemistry, Chemistry Department, Moscow State University, Leninskie Gory 1, 119992 Moscow, Russia.
authors.forename: Irina F
authors.initials: IF
authors.lastname: Seregina
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.
authors.forename: Mathea S
authors.initials: MS
authors.lastname: Galanski
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria; Vernadsky Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences, Kosygin Str. 19, 119991 Moscow, Russia. Electronic address: andrei.timerbaev@univie.ac.at.
authors.forename: Andrei R
authors.initials: AR
authors.lastname: Timerbaev
authors.affiliation: Division of Analytical Chemistry, Chemistry Department, Moscow State University, Leninskie Gory 1, 119992 Moscow, Russia; Institute for Spectroscopy, Russian Academy of Sciences, Fizicheskaya 5, 142190 Troitsk (Moscow Region), Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Bolshov
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D001798:Blood Proteins / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D008024:Ligands; D013058:Mass Spectrometry; D010984:Platinum / Q000097:blood / Q000737:chemistry; D017671:Platinum Compounds / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; D008024:Ligands; D017671:Platinum Compounds; D012709:Serum Albumin; D010984:Platinum
keywords: Albumin; Human serum; ICP–MS; Metallodrugs