title: Improved selectivity of mIBG uptake into neuroblastoma cells in vitro and in vivo by inhibition of organic cation transporter 3 uptake using clinically approved corticosteroids.
abstract: Radiolabeled meta-iodobenzylguanidine (mIBG) is used for imaging and therapy of neuroblastoma as well as pheochromocytoma. However, non-tumorous tissues also incorporate mIBG mainly by organic cation transporters (OCTs). In this study, we tested different clinically approved corticosteroids as potential inhibitors of the OCT3-mediated uptake in vitro and in vivo, to achieve a more selective mIBG tumor uptake.
  
  
  
  The in vitro incorporation of [(3)H]norepinephrine ([(3)H]NE), [(3)H]dopamine ([(3)H]DA) and [(123)I]mIBG in neuroblastoma cells (SK-N-SH, Kelly, IMR-32) and in HEK-293 cells transfected with human OCT3 was measured with and without supplemental corticosteroids (hydrocortisone, prednisolone, dexamethasone, corticosterone). The in vivo biodistribution of [(123)I]mIBG in absence and presence of corticosteroids was studied in non-tumor bearing NOD scid gamma mice. Retrospectively, we selected patients with and without corticosteroid treatment prior to [(123)I]mIBG scintigraphy.
  
  
  
  A concentration-dependent inhibitory effect of different corticosteroids on the [(3)H]NE and [(3)H]DA uptake via OCT3 was illustrated in vitro. The highest OCT3 inhibition was observed for corticosterone, but clinically used corticosteroids, showed also promising inhibitory effects. In contrast, the uptake in neuroblastoma cells was reduced only moderately. Hydrocortisone or prednisolone had only minor effects on [(123)I]mIBG uptake of both neuroblastoma cells, but reduced uptake in OCT3 expressing cells significantly. In mice tissues, [(123)I]mIBG uptake was inhibited by corticosteroids especially in the small intestine and kidney. Finally, in one patient with hydrocortisone treatment performed prior to [(123)I]mIBG scan, heart and liver uptake was reduced compared to untreated patients.
  
  
  
  The OCT3 is widely spread in many organs and responsible for non-targeted uptake of radiolabeled mIBG. In our study, clinically approved corticosteroids inhibited mIBG uptake in OCT3 expressing cells effectively, whereas tracer accumulation in NT (norepinephrine transporter) expressing neuroblastoma cells showed consistency. We conclude, that a single dose of hydrocortisone or prednisolone prior to [(123)I]mIBG scintigraphy may improve specificity and reduce radiation dose to non-target organs.
authors.affiliation: Eberhard Karls University, Children's Hospital, Department I, General Pediatrics & Hematology/Oncology, Tuebingen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bayer
authors.affiliation: Eberhard Karls University, Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Tuebingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Eberhard Karls University, Department of Radiology, Nuclear Medicine, Tuebingen, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dittmann
authors.affiliation: Eberhard Karls University, Children's Hospital, Department I, General Pediatrics & Hematology/Oncology, Tuebingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Eberhard Karls University, Children's Hospital, Department I, General Pediatrics & Hematology/Oncology, Tuebingen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Bruchelt
authors.affiliation: Eberhard Karls University, Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Tuebingen, Germany; Eberhard Karls University, Department of Radiology, Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, D-72076 Tuebingen, Germany. Electronic address: alexander.sauter.imaging@gmail.com.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Sauter
mesh_terms: D019797:3-Iodobenzylguanidine / Q000378:metabolism* / Q000493:pharmacokinetics; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D017277:Drug Approval; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D011239:Prednisolone / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000305:Adrenal Cortex Hormones; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D019797:3-Iodobenzylguanidine; D011239:Prednisolone; D006854:Hydrocortisone
keywords: Corticosteroids; MIBG; Neuroblastoma; Norepinephrine Transporter; OCT3 transporter; Pheochromocytoma