Characterization and Evaluation of 64Cu-Labeled A20FMDV2 Conjugates for Imaging the Integrin αvβ6

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• 作者：Lina Y. Hu (1)
  Nadine Bauer (1)
  Leah M. Knight (1)
  Zibo Li (2)
  Shuanglong Liu (2)
  Carolyn J. Anderson (3)
  Peter S. Conti (2)
  Julie L. Sutcliffe (1) (4) (5)
  
• 关键词：Integrin αvβ6 ; Copper ; 64 ; PET imaging
• 刊名：Molecular Imaging and Biology
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：16
• 期：4
• 页码：567-577
• 全文大小：2,790 KB
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• 作者单位：Lina Y. Hu (1)
  Nadine Bauer (1)
  Leah M. Knight (1)
  Zibo Li (2)
  Shuanglong Liu (2)
  Carolyn J. Anderson (3)
  Peter S. Conti (2)
  Julie L. Sutcliffe (1) (4) (5)
  
  1. Department of Biomedical Engineering, University of California Davis, Davis, CA, USA
  2. Department of Radiology, University of Southern California, Los Angeles, CA, USA
  3. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA
  4. Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, School of Medicine, Research II, 4625 2nd Ave, Sacramento, CA, 95817, USA
  5. Center for Molecular and Genomic Imaging, University of California Davis, Davis, CA, USA
  
• ISSN：1860-2002

文摘

Purpose The integrin αvβ6 is overexpressed in a variety of aggressive cancers and serves as a prognosis marker. This study describes the conjugation, radiolabeling, and in vitro and in vivo evaluation of four chelators to determine the best candidate for 64Cu radiolabeling of A20FMDV2, an αvβ6 targeting peptide. Procedures Four chelators were conjugated onto PEG28-A20FMDV2 (1): 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and 4,4-((3,6,10,13,16,19-hexazazbicyclo[6.6.6]ico-sane-1,8-diylbis(aza-nediyl))bis(methylene)dibenzoic acid (BaBaSar). All peptides were radiolabeled with 64Cu in ammonium acetate buffer at pH?6 and formulated to pH?7.2 in PBS for use. The radiotracers were evaluated using in vitro cell binding and internalization assays and serum stability assays. In vivo studies conducted include blocking, biodistribution, and small animal PET imaging. Autoradiography and histology were also conducted. Results All radiotracers were radiolabeled in good radiochemical purity (>95?%) under mild conditions (37-0?°C for 15?min) with high specific activity (0.58-.60?Ci/μmol). All radiotracers demonstrated αvβ6-directed cell binding (>46?%) with similar internalization levels (>23?%). The radiotracers 64Cu-CB-TE1A1P-1 and 64Cu-BaBaSar-1 showed improved specificity for the αvβ6 positive tumor in vivo over 64Cu-DOTA-1 and 64Cu-NOTA-1 (+/?tumor uptake ratios-.82-/--.44, 3.82?±-.41, 2.58?±-.58, and 1.29?±-.14, respectively). Of the four radiotracers, 64Cu-NOTA-1 exhibited the highest liver uptake (10.83?±-.1?% ID/g at 4?h). Conclusions We have successfully conjugated, radiolabeled, and assessed the four chelates CB-TE1A1P, DOTA, NOTA, and BaBaSar both in vitro and in vivo. However, the data suggests no clear “best candidate-for the 64Cu-radiolabeling of A20FMDV2, but instead a trade-off between the different properties (e.g., stability, selectivity, pharmacokinetics, etc.) with no obvious effects of the individual chelators.