title: The impact of weakly bound ⁸⁹Zr on preclinical studies: non-specific accumulation in solid tumors and aspergillus infection.
abstract: Preclinical studies involving (89)Zr often report significant bone accumulation, which is associated with dissociation of the radiometal from the tracer. However, experiments determining the uptake of unbound (89)Zr in disease models are not performed as routine controls. The purpose of the present study was to investigate the impact of free or weakly bound (89)Zr on PET quantifications in disease models, in order to determine if such control experiments are warranted.
  
  
  METHODS
  Chemical studies were carried out to find a (89)Zr compound that would solubilize the (89)Zr as a weak chelate, thus mimicking free or weakly bound (89)Zr released in circulation. (89)Zr oxalate had the desired characteristics, and was injected into mice bearing FaDu and HT29 solid tumor xenografts, and mice infected in the lungs with the mold Aspergillus fumigatus, as well as in healthy controls (naïve). PET/CT or PET/MR imaging followed to quantify the distribution of the radionuclide in the disease models.
  
  
  RESULTS
  (89)Zr oxalate was found to have a plasma half-life of 5.1 ± 2.3 h, accumulating mainly in the bones of all animals. Both tumor types accumulated (89)Zr on the order of 2-4 %ID/cm(3), which is comparable to EPR-mediated accumulation of certain species. In the aspergillosis model, the concentration of (89)Zr in lung tissue of the naïve animals was 6.0 ± 1.1 %ID/g. This was significantly different from that of the animals with advanced disease, showing 11.6 ± 1.8 %ID/g.
  
  
  CONCLUSIONS
  Given the high levels of (89)Zr accumulation in the disease sites in the present study, we recommend control experiments mapping the biodistribution of free (89)Zr in any preclinical study employing (89)Zr where bone uptake is observed. Aqueous (89)Zr oxalate appears to be a suitable compound for such studies. This is especially relevant in studies where the tracer accumulation is based upon passive targeting, such as EPR.
authors.affiliation: The Hevesy Laboratory, DTU Nutech, Technical University of Denmark; Center for Nanomedicine and Theranostics, Technical University of Denmark.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Severin
authors.affiliation: Dept. of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet and Cluster for Molecular Imaging, Faculty of Health Science, University of Copenhagen, Denmark.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Jørgensen
authors.affiliation: Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiehr
authors.affiliation: Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Rolle
authors.affiliation: Dept. of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet and Cluster for Molecular Imaging, Faculty of Health Science, University of Copenhagen, Denmark; Center for Nanomedicine and Theranostics, Technical University of Denmark; Department of Micro- and Nanotechnology, DTU Nanotech, Technical University of Denmark.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Hansen
authors.affiliation: Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Maurer
authors.affiliation: University Duisburg-Essen, University Hospital, Institute for Experimental Immunology and Imaging, Essen, Germany.
authors.forename: Mike
authors.initials: M
authors.lastname: Hasenberg
authors.affiliation: Werner Siemens Imaging Center, Department for Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Pichler
authors.affiliation: Dept. of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet and Cluster for Molecular Imaging, Faculty of Health Science, University of Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kjær
authors.affiliation: The Hevesy Laboratory, DTU Nutech, Technical University of Denmark; Center for Nanomedicine and Theranostics, Technical University of Denmark. Electronic address: atije@dtu.dk.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000378:metabolism*; D001232:Aspergillus fumigatus / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008168:Lung / Q000382:microbiology; D051379:Mice; D019815:Oxalic Acid / Q000737:chemistry; D004369:Pentetic Acid / Q000737:chemistry; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry; D015040:Zirconium / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D008024:Ligands; D011868:Radioisotopes; D014867:Water; D004369:Pentetic Acid; D019815:Oxalic Acid; D015040:Zirconium
keywords: Aspergillus fumigatus; Cancer; Infection; Mouse model; PET/MR; Zr-89