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A Clinical Wide-Field Fluorescence Endoscopic Device for Molecular Imaging Demonstrating Cathepsin Protease Activity in Colon Cancer

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Abstract

Purpose

Early and effective detection of cancers of the gastrointestinal tract will require novel molecular probes and advances in instrumentation that can reveal functional changes in dysplastic and malignant tissues. Here, we describe adaptation of a wide-field clinical fiberscope to perform wide-field fluorescence imaging while preserving its white-light capability for the purpose of providing wide-field fluorescence imaging capability to point-of-care microscopes.

Procedures

We developed and used a fluorescent fiberscope to detect signals from a quenched probe, BMV109, that becomes fluorescent when cleaved by, and covalently bound to, active cathepsin proteases. Cathepsins are expressed in inflammation- and tumor-associated macrophages as well as directly from tumor cells and are a promising target for cancer imaging. The fiberscope has a 1-mm outer diameter enabling validation via endoscopic exams in mice, and therefore we evaluated topically applied BMV109 for the ability to detect colon polyps in an azoxymethane-induced colon tumor model in mice.

Results

This wide-field endoscopic imaging device revealed consistent and clear fluorescence signals from BMV109 that specifically localized to the polypoid regions as opposed to the normal adjacent colon tissue (p < 0.004) in the murine colon carcinoma model.

Conclusions

The sensitivity of detection of BMV109 with the fluorescence fiberscope suggested utility of these tools for early detection at hard-to-reach sites. The fiberscope was designed to be used in conjunction with miniature, endoscope-compatible fluorescence microscopes for dual wide-field and microscopic cancer detection.

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Acknowledgments

The authors thank the Stanford Small Animal Imaging Facility for resources and technical support. We would also like to thank Pankaj Pasricha, Martijn Verdoes, Laura Edgington, James Amos-Landgraff, Laura Bronsart, Bonnie King, and the laboratory of Lawrence Marnett for equipment, assistance, and discussions aiding in the development of our imaging system. This work was supported in part by the National Cancer Institute (U54 CA136465 and P50 CA114747), the Canary Foundation, and a generous gift from the Chambers Family Foundation for Excellence in Pediatric Research. Steven Sensarn was supported by the Stanford Cancer Imaging Training fellowship from the NCI (5 T32 CA 9695-19). Cristina Zavaleta was supported by the National Cancer Institute of the National Institutes of Health under Award Number K22 CA160834.

Author information

Correspondence to Christopher H. Contag.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable institutional and/or national guidelines for the care and use of animals were followed.

Additional information

Steven Sensarn and Cristina L. Zavaleta contributed equally to this work.

Electronic Supplementary Material

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Sensarn, S., Zavaleta, C.L., Segal, E. et al. A Clinical Wide-Field Fluorescence Endoscopic Device for Molecular Imaging Demonstrating Cathepsin Protease Activity in Colon Cancer. Mol Imaging Biol 18, 820–829 (2016). https://doi.org/10.1007/s11307-016-0956-7

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Key words

  • Optical imaging
  • Optical probes
  • Endoscopy
  • Fluorescence
  • Imaging systems
  • Medical imaging
  • Fiber optics
  • Biomedical optics