title: 67Cu-Radiolabeling of a multimeric RGD peptide for αVβ3 integrin-targeted radionuclide therapy: stability, therapeutic efficacy, and safety studies in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for αVβ3 integrin-targeted internal radiotherapy.
authors.affiliation: 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.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Jin
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohya
authors.forename: Mélissa
authors.initials: M
authors.lastname: Degardin
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Higashi
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D004355:Drug Stability; D005260:Female; D005909:Glioblastoma / Q000532:radiotherapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D009942:Organometallic Compounds / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D011879:Radiotherapy Dosage; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D003301:Copper Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid