title: Molecular mass spectrometry in metallodrug development: a case of mapping transferrin-mediated transformations for a ruthenium(III) anticancer drug.
abstract: Electrospray ionization mass spectrometry (ESI-MS) techniques have been used to characterize the speciation of a Ru(III) anticancer drug, indazolium trans-[tetrachloridobis(1H-indazole) ruthenate(III)], upon its binding to transferrin and the impact of cellular reducing components on drug-transferrin adducts. Using time-of-flight ESI-MS, the polymorphism of apo- (iron-free) and holo-form (iron-saturated) of the protein was confirmed. While the ruthenium moieties bound to each of five isoforms under simulated extracellular conditions are essentially identical in numbers for apo- and holo-transferrin, distinct differences were found in the composition of Ru(III) species attached to either of the protein forms, which are dominated by differently coordinated aquated complexes. On the other hand, at least one of the RuN bonds in metal-organic framework remains intact even after prolonged interaction with the protein. Triple quadrupole tandem ESI-MS measurements demonstrated that the ruthenium species released from drug adducts with holo-transferrin in simulated cancer cytosol are underwent strong ligand exchange (as compared to the protein-bound forms) but most strikingly, they contain the metal center in the reduced Ru(II) state. In vitro probing the extra- and intracellular interactions of promising Ru(III) drug candidate performed by ESI-MS is thought to shed light on the transportation to tumor cells by transferrin and on the activation to more reactive species by the reducing environment of solid tumors.
authors.affiliation: Chair of Analytical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Jarosz
authors.affiliation: Chair of Analytical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland. Electronic address: mmatczuk@ch.pw.edu.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Matczuk
authors.affiliation: Chair of Analytical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pawlak
authors.affiliation: Vernadsky Institute of Geochemistry and Analytical Chemistry, Russian Academy of Sciences, Kosygin St. 19, 119991 Moscow, Russian Federation.
authors.forename: Andrei R
authors.initials: AR
authors.lastname: Timerbaev
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D001692:Biological Transport; D001711:Biotransformation; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008970:Molecular Weight; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012428:Ruthenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007191:Indazoles; D009942:Organometallic Compounds; D014168:Transferrin; C000599670:tetrachloridobis(1H-indazole)ruthenate(III); D012428:Ruthenium
keywords: Cell processing; Electrospray ionization mass spectrometry; Ruthenium anticancer drugs; Transferrin