title: Micro-positron emission tomography/contrast-enhanced computed tomography imaging of orthotopic pancreatic tumor-bearing mice using the αvβ₃ integrin tracer ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄.
abstract: The purpose of this study was to develop a clinically relevant orthotopic xenotransplantation model of pancreatic cancer and to perform a preclinical evaluation of a new positron emission tomography (PET) imaging probe, ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄ peptide (⁶⁴Cu-RAFT-RGD), using this model. Varying degrees of αvβ₃ integrin expression in several human pancreatic cancer cell lines were examined by flow cytometry and Western blotting. The cell line BxPC-3, which is stably transfected with a red fluorescence protein (RFP), was used for surgical orthotopic implantation. Orthotopic xenograft was established in the pancreas of recipient nude mice. An in vivo probe biodistribution and receptor blocking study, preclinical PET imaging coregistered with contrast-enhanced computed tomography (CECT) comparing ⁶⁴Cu-RAFT-RGD and ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) accumulation in tumor, postimaging autoradiography, and histologic and immunohistochemical examinations were done. Biodistribution evaluation with a blocking study confirmed that efficient binding of probe to tumor is highly αvβ₃ integrin specific. ⁶⁴Cu-RAFT-RGD PET combined with CECT provided for precise and easy detection of cancer lesions. Autoradiography, histologic, and immunohistochemical examinations confirmed the accumulation of ⁶⁴Cu-RAFT-RGD in tumor versus nontumor tissues. In comparative PET studies, ⁶⁴Cu-RAFT-RGD accumulation provided better tumor contrast to background than ¹⁸F-FDG. Our results suggest that ⁶⁴Cu-RAFT-RGD PET imaging is potentially applicable for the diagnosis of αvβ₃ integrin-expressing pancreatic tumors.
authors: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. winn@nirs.go.jp
authors: Winn
authors: W
authors: Aung
authors: Zhao-Hui
authors: ZH
authors: Jin
authors: Takako
authors: T
authors: Furukawa
authors: Michael
authors: M
authors: Claron
authors: Didier
authors: D
authors: Boturyn
authors: Chizuru
authors: C
authors: Sogawa
authors: Atsushi B
authors: AB
authors: Tsuji
authors: Hidekatsu
authors: H
authors: Wakizaka
authors: Toshimitsu
authors: T
authors: Fukumura
authors: Yasuhisa
authors: Y
authors: Fujibayashi
authors: Pascal
authors: P
authors: Dumy
authors: Tsuneo
authors: T
authors: Saga
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000493:pharmacokinetics; D003301:Copper Radioisotopes; D005260:Female; D064593:Heterografts; D006651:Histocytochemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis* / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D014018:Tissue Distribution; D055114:X-Ray Microtomography / Q000379:methods*
chemical_list: C560405:64Cu-cyclam-RAFT-cyclo(arginyl-glycyl-aspartyl-phenylalanyl-lysyl)4; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals