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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ~(64)Cu-SarAr immunoconjugates
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Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ~(64)Cu-SarAr immunoconjugates

机译：〜（64）Cu-SarAr免疫偶联物对神经母细胞瘤和黑色素瘤的正电子发射断层扫描（PET）成像

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The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement ~(18)F-FDG. Copper-64 (~(64)Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr(1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) for use in developing a new class of tumor-specific ~(64)Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiola beling with ~(64)Cu resulted in ＞ 95% of the ~(64)Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after ~(64)Cu labeling. Solid-phase radioimmuno assays and intact cell-binding assays confirmed retention of bio activity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xeno graft was significantly lower (＜ 5% injected dose per gram). Mi-croPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The ~(64)Cu-SarAr-mAb system described here is potentially applicable to ~(64)Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.
机译：正电子发射断层扫描（PET）的发展取决于新的放射性示踪剂的发展，它将补充〜（18）F-FDG。铜64（〜（64）Cu）是一种有前途的PET放射性核素，特别是用于抗体靶向成像，但是常规螯合物的体内高稳定性限制了其临床应用。这项工作的目的是评估新型螯合剂SarAr（1-N-（4-氨基苄基）-3，6,10,13,16,19-六氮杂双环[6.6.6]-二十烷-1,8-二胺）用于开发新型的肿瘤特异性〜（64）Cu放射性药物，用于对神经母细胞瘤和黑色素瘤进行成像。抗GD2单克隆抗体（mAb）14.G2a及其嵌合衍生物ch14.18靶向在神经母细胞瘤和黑色素瘤中过表达的二唾液酸神经节苷脂。使用碳二亚胺偶联将两个mAb偶联至SarAr。 Radiola与〜（64）Cu螯合导致免疫结合物螯合〜95％的〜（64）Cu。常规获得至少10μCi/μg（1 Ci = 37 GBq）的比活，〜（64）Cu标记后无需额外纯化。固相放射免疫测定和完整的细胞结合测定证实了生物活性的保留。携带s.c.的无胸腺裸鼠的生物分布研究神经母细胞瘤（IMR-6，NMB-7）和黑色素瘤（M21）异种移植物显示，在注射后24小时内，每克注射剂量的15-20％累积在肿瘤中，而每克注射剂量的5-10％累积在肿瘤中。肝脏，其价值低于其他螯合剂的典型价值。 GD2阴性肿瘤异种移植物的摄取显着降低（每克＜5％注射剂量）。 Mi-croPET成像证实在GD-2阳性肿瘤中显着摄取了示踪剂，而在GD-2阴性肿瘤和非靶组织（例如肝脏）中摄取了最少的示踪剂。此处介绍的〜（64）Cu-SarAr-mAb系统可能适用于使用多种抗体或基于肽的成像剂的〜（64）Cu-PET成像。

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