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  • [Clin Cancer Res.] Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer.

    University of Wisconsin-Madison / Weibo Cai*

  • 출처
    Clin Cancer Res.
  • 등재일
    2016 Aug 1
  • 저널이슈번호
    22(15):3821-30. doi: 10.1158/1078-0432.CCR-15-2054. Epub 2016 Mar 29.
  • 내용

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    Abstract
    PURPOSE:
    Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly specific noninvasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention.

    EXPERIMENTAL DESIGN:
    A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bio-orthogonal "click" reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with (64)Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors.

    RESULTS:
    PET imaging of BXPC-3 (TF/CD105(+/+)) xenograft tumors with (64)Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 ± 3.2 %ID/g; n = 4; SD) at 30 hours postinjection, as compared with each of their monospecific Fab tracers (12.5 ± 1.4 and 7.1 ± 2.6 %ID/g; n = 3; SD). In addition, the activity-concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 ± 9.4 at 30 hours postinjection.; n = 4; SD). Furthermore, (64)Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 ± 4.9 %ID/g at 30 hours postinjection and tumor/muscle ratio of 72.3 ± 46.7.

    CONCLUSIONS:
    This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response.

     

    Author information

    Luo H1, England CG2, Shi S3, Graves SA2, Hernandez R2, Liu B4, Theuer CP5, Wong HC4, Nickles RJ2, Cai W6.
    1Department of Radiology, University of Wisconsin-Madison, Wisconsin.
    2Department of Medical Physics, University of Wisconsin-Madison, Wisconsin.
    3Materials Science Program, University of Wisconsin-Madison, Wisconsin.
    4Altor BioSciences, Miramar, Florida.
    5TRACON Pharmaceuticals, Inc., San Diego, California.
    6Department of Radiology, University of Wisconsin-Madison, Wisconsin. Department of Medical Physics, University of Wisconsin-Madison, Wisconsin. Materials Science Program, University of Wisconsin-Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. wcai@uwhealth.org.

     

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