Helge Thisgaard1, Birgitte Brinkmann Olsen2, Johan Hygum Dam2, Peter Bollen3, Jan Mollenhauer4, Poul Flemming Høilund-Carlsen5. 1. PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark Institute of Clinical Research, University of Southern Denmark, Odense, Denmark Helge.Thisgaard@rsyd.dk. 2. PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark. 3. Biomedical Laboratory, University of Southern Denmark, Odense, Denmark; and. 4. Lundbeckfonden Center of Excellence NanoCAN and Molecular Oncology Group, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark. 5. PET & Cyclotron Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Abstract
UNLABELLED: The somatostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, (57)Co-labeled DOTATOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron-based radionuclide therapy. METHODS: Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with (57)Co or (58m)Co for SPECT or Auger electron-based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of (58m)Co-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of (111)In- and (177)Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumor mouse model. RESULTS: All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular internalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. (58m)Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than (111)In- and (177)Lu-DOTATATE. The in vivo pharmacokinetic studies showed a high level of receptor-specific tumor uptake. CONCLUSION: All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, (58m)Co-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases.
UNLABELLED: The somatostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, (57)Co-labeled DOTATOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron-based radionuclide therapy. METHODS:Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with (57)Co or (58m)Co for SPECT or Auger electron-based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of (58m)Co-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of (111)In- and (177)Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumormouse model. RESULTS: All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular internalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. (58m)Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than (111)In- and (177)Lu-DOTATATE. The in vivo pharmacokinetic studies showed a high level of receptor-specific tumor uptake. CONCLUSION: All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, (58m)Co-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases.
Authors: H F Valdovinos; R Hernandez; S Graves; P A Ellison; T E Barnhart; C P Theuer; J W Engle; W Cai; R J Nickles Journal: Appl Radiat Isot Date: 2017-09-06 Impact factor: 1.513
Authors: Javad Garousi; Ken G Andersson; Johan H Dam; Birgitte B Olsen; Bogdan Mitran; Anna Orlova; Jos Buijs; Stefan Ståhl; John Löfblom; Helge Thisgaard; Vladimir Tolmachev Journal: Sci Rep Date: 2017-07-20 Impact factor: 4.379