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Near-Infrared Fluorescence Imaging of Both Colorectal Cancer and Ureters Using a Low-Dose Integrin Targeted Probe

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Irradical tumor resections and iatrogenic ureteral injury remain a significant problem during lower abdominal surgery. The aim of the current study was to intraoperatively identify both colorectal tumors and ureters in subcutaneous and orthotopic animal models using cRGD-ZW800-1 and near-infrared (NIR) fluorescence.

Methods

The zwitterionic fluorophore ZW800-1 was conjugated to the tumor specific peptide cRGD (targeting integrins) and to the a-specific peptide cRAD. One nmol cRGD-ZW800-1, cRAD-ZW800-1, or ZW800-1 alone was injected in mice bearing subcutaneous HT-29 human colorectal tumors. Subsequently, cRGD-ZW800-1 was injected at dosages of 0.25 and 1 nmol in mice bearing orthotopic HT-29 tumors transfected with luciferase2. In vivo biodistribution and ureteral visualization were investigated in rats. Fluorescence was measured intraoperatively at several time points after probe administration using the FLARE imaging system.

Results

Both subcutaneous and orthotopic tumors could be clearly identified using cRGD-ZW800-1. A significantly higher signal-to-background ratio was observed in mice injected with cRGD-ZW800-1 (2.42 ± 0.77) compared with mice injected with cRAD-ZW800-1 or ZW800-1 alone (1.21 ± 0.19 and 1.34 ± 0.19, respectively) when measured at 24 h after probe administration. The clearance of cRGD-ZW800-1 permitted visualization of the ureters and also generated minimal background fluorescence in the gastrointestinal tract.

Conclusions

This study appears to be the first to demonstrate both clear tumor demarcation and ureteral visualization after a single intravenous injection of a targeted NIR fluorophore. As a low dose of cRGD-ZW800-1 provided clear tumor identification, clinical translation of these results should be possible.

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Acknowledgment

We thank Hendrica A. J. M. Prevoo for her contribution the histological analysis and David J. Burrington, Jr. for editing. This work was supported in part by the National Institutes of Health Grant R01-CA-115296, R01-EB-011523, and R01-EB-010022, Dutch Cancer Society Grant UL2010-4732, and the “drie lichten” foundation; the content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was performed within the framework of the Center of Translational Molecular Medicine (project MUSIS, Grant 03O-202-04 and DeCoDe project, Grant 03O-101). Joost van der Vorst is an MD-medical research trainee funded by The Netherlands Organisation for Health Research and Development (Grant 92003593).

Disclosures

Floris P. R. Verbeek, MSc, Joost R. van der Vorst, MD, Quirijn R. J. G. Tummers, MD, Martin C. Boonstra, BSc, Karien E. de Rooij, PhD, Clemens W. G. M. Löwik, PhD, A. Rob P. M. Valentijn, PhD, Cornelis J. H. van de Velde, MD, PhD, Hak Soo Choi, PhD, Alexander L. Vahrmeijer, MD, PhD have nothing to disclose and John V. Frangioni, MD, PhD FLARE™ technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. Dr. Frangioni has started three for-profit companies, Curadel, Curadel ResVet Imaging, and Curadel Surgical Innovations, which has optioned FLARE™ technology for potential licensing from Beth Israel Deaconess Medical Center.

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Authors and Affiliations

  1. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Floris P. R. Verbeek MSc, Joost R. van der Vorst MD, Quirijn R. J. G. Tummers MD, Martin C. Boonstra BSc, Cornelis J. H. van de Velde MD, PhD & Alexander L. Vahrmeijer MD, PhD

  2. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

    Karien E. de Rooij PhD & Clemens W. G. M. Löwik PhD

  3. Clinical Pharmacology and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    A. Rob P. M. Valentijn PhD

  4. Percuros B.V., Leiden, The Netherlands

    Karien E. de Rooij PhD

  5. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA

    Hak Soo Choi PhD & John V. Frangioni MD, PhD

  6. Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA

    John V. Frangioni MD, PhD

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  1. Floris P. R. Verbeek MSc
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Corresponding author

Correspondence to Alexander L. Vahrmeijer MD, PhD.

Additional information

Floris P. R. Verbeek and Joost R. van der Vorst contributed equally to this work and share first-authorship.

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Verbeek, F.P.R., van der Vorst, J.R., Tummers, Q.R.J.G. et al. Near-Infrared Fluorescence Imaging of Both Colorectal Cancer and Ureters Using a Low-Dose Integrin Targeted Probe. Ann Surg Oncol 21 (Suppl 4), 528–537 (2014). https://doi.org/10.1245/s10434-014-3524-x

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