Bayer Melanie, Schmitt Julia, Dittmann Helmut, Handgretinger Rupert, Bruchelt Gernot, Sauter Alexander W
Eberhard Karls University, Children's Hospital, Department I, General Pediatrics & Hematology/Oncology, Tuebingen, Germany.
Eberhard Karls University, Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Tuebingen, Germany.
Nucl Med Biol. 2016 Sep;43(9):543-551. doi: 10.1016/j.nucmedbio.2016.05.013. Epub 2016 May 27.
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.
放射性标记的间碘苄胍（mIBG）用于神经母细胞瘤以及嗜铬细胞瘤的成像和治疗。然而，非肿瘤组织也主要通过有机阳离子转运体（OCTs）摄取mIBG。在本研究中，我们测试了不同的临床批准的皮质类固醇作为OCT3介导摄取的潜在抑制剂，以实现更具选择性的mIBG肿瘤摄取。
在有和没有补充皮质类固醇（氢化可的松、泼尼松龙、地塞米松、皮质酮）的情况下，测量神经母细胞瘤细胞（SK-N-SH、凯利、IMR-32）和转染了人OCT3的HEK-293细胞中[³H]去甲肾上腺素（[³H]NE）、[³H]多巴胺（[³H]DA）和[¹²³I]mIBG的体外摄取。在无肿瘤的NOD scid gamma小鼠中研究了有无皮质类固醇时[¹²³I]mIBG的体内生物分布。回顾性地，我们选择了在[¹²³I]mIBG闪烁扫描前接受和未接受皮质类固醇治疗的患者。
体外显示不同皮质类固醇对通过OCT3摄取[³H]NE和[³H]DA具有浓度依赖性抑制作用。皮质酮观察到最高的OCT3抑制，但临床使用的皮质类固醇也显示出有希望的抑制作用。相比之下，神经母细胞瘤细胞中的摄取仅适度降低。氢化可的松或泼尼松龙对两种神经母细胞瘤细胞的[¹²³I]mIBG摄取只有轻微影响，但显著降低了表达OCT3的细胞中的摄取。在小鼠组织中，[¹²³I]mIBG摄取受到皮质类固醇的抑制，尤其是在小肠和肾脏中。最后，在一名在[¹²³I]mIBG扫描前接受氢化可的松治疗的患者中，与未治疗的患者相比，心脏和肝脏摄取减少。
OCT3广泛分布于许多器官，负责放射性标记的mIBG的非靶向摄取。在我们的研究中，临床批准的皮质类固醇有效地抑制了表达OCT3的细胞中mIBG的摄取，而在表达去甲肾上腺素转运体（NT）的神经母细胞瘤细胞中的示踪剂积累表现一致。我们得出结论，在[¹²³I]mIBG闪烁扫描前单次给予氢化可的松或泼尼松龙可能会提高特异性并减少对非靶器官的辐射剂量。
