title: αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4.
abstract: The transmembrane cell adhesion receptor αVβ3 integrin (αVβ3) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer (64)Cu-cyclam-RAFT-c(-RGDfK-)4, which successfully captured αVβ3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established αVβ3-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 with ascending peptide doses (0.25-10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes-24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4, respectively. Peptide dose study showed that the tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a saturation of αVβ3 with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37-74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 Our study demonstrates the therapeutic efficacy and safety of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 for αVβ3-targeted radionuclide therapy. (64)Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076-85. ©2016 AACR.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. zhaohui@nirs.go.jp.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Jin
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Département de Chimie Moléculaire-UMR CNRS 5250, Université Grenoble Alpes, Grenoble, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Degardin
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Sugyo
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Atsushi B
authors.initials: AB
authors.lastname: Tsuji
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Département de Chimie Moléculaire-UMR CNRS 5250, Université Grenoble Alpes, Grenoble, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.affiliation: École Nationale Supérieure de Chimie de Montpellier, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Dumy
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011874:Radiometry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C560405:64Cu-cyclam-RAFT-cyclo(arginyl-glycyl-aspartyl-phenylalanyl-lysyl)4; D056831:Coordination Complexes; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic