title: Labeling and preliminary in vivo assessment of niobium-labeled radioactive species: A proof-of-concept study.
abstract: The application of radionuclide-labeled biomolecules such as monoclonal antibodies or antibody fragments for imaging purposes is called immunoscintigraphy. More specifically, when the nuclides used are positron emitters, such as zirconium-89, the technique is referred to as immuno-PET. Currently, there is an urgent need for radionuclides with a half-life which correlates well with the biological kinetics of the biomolecules under question and which can be attached to the proteins by robust labeling chemistry. (90)Nb is a promising candidate for in vivo immuno-PET, due its half-life of 14.6h and low β(+) energy of Emean=0.35MeV per decay. (95)Nb on the other hand, is a convenient alternative for longer-term ex vivo biodistribution studies, due to its longer half-life of (t½=35days) and its convenient, lower-cost production (reactor-based production). In this proof-of-principle work, the monoclonal antibody bevacizumab (Avastin(®)) was labeled with (95/90)Nb and in vitro and in vivo stability was evaluated in normal Swiss mice and in tumor-bearing SCID mice. Initial ex vivo experiments with (95)Nb-bevacizumab showed adequate tumor uptake, however at the same time high uptake in the liver, spleen and kidneys was observed. In order to investigate whether this behavior is due to instability of (⁎)Nb-bevacizumab or to the creation of other (⁎)Nb species in vivo, we performed biodistribution studies of (95)Nb-oxalate, (95)Nb-chloride and (95)Nb-Df. These potential metabolite species did not show any specific uptake, apart from bone accumulation for (95)Nb-oxalate and (95)Nb-chloride, which, interestingly, may serve as an "indicator" for the release of (90)Nb from labeled biomolecules. Concerning the initial uptake of (95)Nb-bevacizumab in non-tumor tissue, biodistribution of a higher specific activity radiolabeled antibody sample did show only negligible uptake in the liver, spleen, kidneys or bones. In-vivo imaging of a tumor-bearing SCID mouse after injection with (90)Nb-bevacizumab was acquired on an experimental small-animal PET camera, and indeed showed localization of the radiotracer in the tumor area. It is the first time that such results are described in the literature, and indicates promise of application of (90)Nb-labeled antibodies for the purposes of immuno-PET.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: varad@lanl.gov.
authors.forename: Valery
authors.initials: V
authors.lastname: Radchenko
authors.affiliation: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. "Demokritos", Athens, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Bouziotis
authors.affiliation: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. "Demokritos", Athens, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Tsotakos
authors.affiliation: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. "Demokritos", Athens, Greece.
authors.forename: Mari
authors.initials: M
authors.lastname: Paravatou-Petsotas
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ana de
authors.initials: Ad
authors.lastname: la Fuente
authors.affiliation: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. "Demokritos", Athens, Greece; Department of Biomedical Engineering, Technological Educational Institute of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Loudos
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. "Demokritos", Athens, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Xanthopoulos
authors.affiliation: Dzhelepov Laboratory of Nuclear Problems, Joint Institute of Nuclear Research, Dubna, Moscow region, Russian Federation.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Filosofov
authors.affiliation: Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Radiopharmaceutical Chemistry, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Eisenhut
authors.affiliation: Institute of Nuclear Materials Science, BR2 Reactor, Radioisotopes and NTD Silicon Production, Belgian Nuclear Research Centre, SCKCEN, Mol, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ponsard
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: frank.roesch@uni-mainz.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Roesch
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry; D003676:Deferoxamine / Q000737:chemistry; D004355:Drug Stability; D005260:Female; D006207:Half-Life; D007553:Isotope Labeling / Q000379:methods*; D051379:Mice; D009556:Niobium / Q000737:chemistry* / Q000493:pharmacokinetics; D010070:Oxalates / Q000737:chemistry; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D014018:Tissue Distribution
chemical_list: D002712:Chlorides; D010070:Oxalates; D011868:Radioisotopes; D009556:Niobium; D000068258:Bevacizumab; D003676:Deferoxamine
keywords: (95/90)Nb; Bevacizumab; Biodistribution; Labeling; PET imaging; VEGFR