title: 213Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts.
abstract: BACKGROUND
  Up to now, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy mainly focused on β-emitting radionuclides. Herein, two new213Bi-labeled agents for PSMA-targeted α therapy of prostate cancer (PCa) are reported.
  
  
  METHODS
  The biodistribution of213Bi-labeled small-molecule inhibitor PSMA I&T and nanobody JVZ-008 was evaluated in mice bearing PSMA-positive LNCaP xenografts. DNA damage response was followed using LNCaP cells and LNCaP xenografts.
  
  
  RESULTS
  In vitro,213Bi-PSMA I&T and213Bi-JVZ-008 therapy of LNCaP cells led to increased number of DNA double-strand breaks (DSBs), detected as 53BP1 and γH2AX nuclear foci. In vivo, tumor uptake of213Bi-PSMA I&T and213Bi-JVZ-008 was 5.75% ± 2.70%ID/g (injected dose per gram) and 2.68% ± 0.56%ID/g, respectively, with similar tumor-to-kidney ratios. Furthermore, both agents induced in vivo DSBs in the tumors, which were detected between 1 hour and 24 hours after injection.213Bi-PSMA I&T induced significantly more DSBs than213Bi-JVZ-008 (p < 0.01).
  
  
  CONCLUSIONS
  213Bi-PSMA I&T and213Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation of213Bi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy.
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .|2 Department of Molecular Genetics, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Julie
authors.initials: J
authors.lastname: Nonnekens
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .|3 Department of Urology, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Kristell L S
authors.initials: KL
authors.lastname: Chatalic
authors.affiliation: 4 Department of Radiology and Nuclear Medicine, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Janneke D M
authors.initials: JD
authors.lastname: Molkenboer-Kuenen
authors.affiliation: 5 Department of Radiation Oncology, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Cecile E M T
authors.initials: CE
authors.lastname: Beerens
authors.affiliation: 6 European Commission, Joint Research Centre , Directorate for Nuclear Safety and Security, Karlsruhe, Germany .
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: 6 European Commission, Joint Research Centre , Directorate for Nuclear Safety and Security, Karlsruhe, Germany .
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.affiliation: 3 Department of Urology, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Joke
authors.initials: J
authors.lastname: Veldhoven-Zweistra
authors.affiliation: 7 Pharmaceutical Radiochemistry, Technische Universität München , Garching, Germany .
authors.forename: Margret
authors.initials: M
authors.lastname: Schottelius
authors.affiliation: 7 Pharmaceutical Radiochemistry, Technische Universität München , Garching, Germany .
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.affiliation: 2 Department of Molecular Genetics, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.affiliation: 3 Department of Urology, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.affiliation: 4 Department of Radiology and Nuclear Medicine, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.affiliation: 1 Department of Radiology and Nuclear Medicine, Erasmus MC , Rotterdam, The Netherlands .
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.affiliation: 4 Department of Radiology and Nuclear Medicine, Radboud University Medical Center , Nijmegen, The Netherlands .
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
mesh_terms: D000818:Animals; D001729:Bismuth / Q000737:chemistry*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D011868:Radioisotopes / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011868:Radioisotopes; C000589188:PSMA1 protein, human; D046988:Proteasome Endopeptidase Complex; D001729:Bismuth
keywords: Bi-213; PSMA; prostate cancer; radionuclide therapy; targeted α therapy