Jin Zhao-Hui, Furukawa Takako, Ohya Tomoyuki, Degardin Mélissa, Sugyo Aya, Tsuji Atsushi B, Fujibayashi Yasuhisa, Zhang Ming-Rong, Higashi Tatsuya, Boturyn Didier, Dumy Pascal, Saga Tsuneo
aDepartment of Molecular Imaging and Theranostics bDepartment of Radiopharmaceuticals Development, National Institutes for Quantum and Radiological Science and Technology (NIRS-QST), Chiba cDepartment of Radiological and Medical Laboratory Sciences, Graduate School of Medicine, Nagoya University, Nagoya dDepartment of Diagnostic Radiology, Kyoto University Hospital, Kyoto, Japan eDepartment of Molecular Chemistry-UMR CNRS 5250, Grenoble Alpes University, Grenoble fMontpellier's National Graduate School of Chemistry, Montpellier, France.
Nucl Med Commun. 2017 Apr;38(4):347-355. doi: 10.1097/MNM.0000000000000646.
Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale production of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets αVβ3 integrin (αVβ3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound.
Cu, produced through the Ni(α, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liquid chromatography and/or thin-layer chromatography. Mice with subcutaneous αVβ3-positive U87MG-glioblastoma xenografts received a single intravenous injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle solution. The tumor volumes were measured, side effects were assessed in terms of body weight, routine hematology, and hepatic and renal functions, and the mouse radiation dosimetry was estimated.
Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochemical purity of 97.9±2.4% and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that observed upon vehicle or peptide control administration, with an estimated tumor-absorbed dose of 0.712 Gy. No significant toxicity was observed in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice.
Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVβ3 integrin-targeted internal radiotherapy.
铜-67（⁶⁷Cu）是用于内照射治疗最有前景的放射性核素之一。在全球范围内，最近启动了几个项目来开发大规模生产⁶⁷Cu的创新方法。受这些项目鼓舞，我们对一种四聚体环状精氨酸-甘氨酸-天冬氨酸（cRGD）肽缀合物cyclam-RAFT-c(-RGDfK-)₄进行了⁶⁷Cu放射性标记，该缀合物可选择性靶向αVβ3整合素，这是一种参与肿瘤侵袭、血管生成和转移的跨膜受体。我们还评估了这种放射性化合物的治疗潜力和安全性。
通过Ni(α, p)⁶⁷Cu反应产生的⁶⁷Cu用于在70°C下对cyclam-RAFT-c(-RGDfK-)₄进行放射性标记10分钟。使用反相高效液相色谱法和/或薄层色谱法评估放射性标记效率和产物稳定性。皮下接种αVβ3阳性U87MG胶质母细胞瘤异种移植物的小鼠接受以下单次静脉注射之一：⁶⁷Cu-cyclam-RAFT-c(-RGDfK-)₄（11.1 MBq）、肽对照或赋形剂溶液。测量肿瘤体积，根据体重、常规血液学以及肝肾功能评估副作用，并估算小鼠辐射剂量学。
制备的⁶⁷Cu-cyclam-RAFT-c(-RGDfK-)₄放射化学纯度为97.9±2.4%，比活度为2.7±0.6 MBq/nmol，在体外和体内血浆中均显示出高稳定性。与给予赋形剂或肽对照相比，单次给予⁶⁷Cu-cyclam-RAFT-c(-RGDfK-)₄导致肿瘤生长明显延迟，估计肿瘤吸收剂量为0.712 Gy。在接受⁶⁷Cu-cyclam-RAFT-c(-RGDfK-)₄治疗的小鼠中未观察到明显毒性。
⁶⁷Cu-cyclam-RAFT-c(-RGDfK-)₄将是一种有前景的用于αVβ3整合素靶向内照射放疗的治疗剂。
