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Beyond the margins: real-time detection of cancer using targeted fluorophores

Key Points

  • Fluorescence imaging can transform the way surgeries are performed, through the intraoperative identification of vital structures, lymph nodes and cancer in real time

  • Near-infrared (NIR) fluorescence is particularly advantageous for use in clinical settings owing to improved depth penetration and low autofluorescence in the NIR wavelength range compared with shorter wavelengths

  • Many targeted NIR fluorophores are currently in preclinical development; however, no cancer-targeted NIR fluorophores or devices for intraoperative NIR fluorescence detection of cancer have received commercial approval for human use

  • Multiple early phase clinical trials are underway to evaluate targeted fluorophores for real-time, intraoperative cancer detection in humans

  • The use of targeted fluorophores for the intraoperative detection of cancer might improve survival rates and functional outcomes in patients with cancer

  • Currently, substantial regulatory challenges and clinical trial considerations constitute barriers for the adoption of fluorescence-guided surgery in clinical settings

Abstract

Over the past two decades, synergistic innovations in imaging technology have resulted in a revolution in which a range of biomedical applications are now benefiting from fluorescence imaging. Specifically, advances in fluorophore chemistry and imaging hardware, and the identification of targetable biomarkers have now positioned intraoperative fluorescence as a highly specific real-time detection modality for surgeons in oncology. In particular, the deeper tissue penetration and limited autofluorescence of near-infrared (NIR) fluorescence imaging improves the translational potential of this modality over visible-light fluorescence imaging. Rapid developments in fluorophores with improved characteristics, detection instrumentation, and targeting strategies led to the clinical testing in the early 2010s of the first targeted NIR fluorophores for intraoperative cancer detection. The foundations for the advances that underline this technology continue to be nurtured by the multidisciplinary collaboration of chemists, biologists, engineers, and clinicians. In this Review, we highlight the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, and consider the unique challenges associated with their effective application in clinical settings.

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Figure 1: NIR fluorescence is more suitable for in vivo imaging applications than visible-light fluorescence.
Figure 2: Targeted fluorophores tested in clinical trials.
Figure 3: Cetuximab-800CW fluorescence in a patient with EGFR-positive head and neck cancer.
Figure 4: Preclinical and clinical development of targeted fluorophores.

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Acknowledgements

R.R.Z. is partially supported by the University of Wisconsin MD/PhD program via T32 GM008692. E.L.R. is supported by NCI 1R01CA190306-01A1 grant. J.M.W. is supported by the NIH/NCI R21CA182953, R21CA179171 and T32CA091078 grants, the Robert Armstrong Research Acceleration Fund and the UAB Comprehensive Cancer Center, and institutional equipment loans from LI–COR Biosciences and Novadaq. A.B.S. and K.W.E. are supported by the Morgridge Institute for Research. J.S.K. and J.P.W. are partially supported by NCI R01-15880 grant. J.S.K. is supported in part by the Headrush Brain Tumour Research Professorship, the NIH R01NS75995 grant, and the Roger Loff Memorial Fund Farming against Brain Cancer. We would like to thank A. Uselmann for reviewing the instrumentation contributions. Special thanks to J. Huston (John Huston Graphic Design, Madison, Wisconsin, USA) for assistance with illustrations and formatting.

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R.R.Z., A.B.S., J.J.G., A.N.P., K.W.E., J.S.K. and J.P.W. researched data for the article, discussed the content, wrote, and edited the manuscript. E.L.R. and J.M.W. edited the manuscript and provided figures. K.W.E., J.S.K. and J.P.W. supervised this work.

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Correspondence to Jamey P. Weichert.

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Competing interests

J.J.G., A.N.P. and J.P.W. declare associations with Cellectar Biosciences. J.P.W. is the inventor of the APC analogues discussed in the Review. K.W.E is a consultant for the Bruker Corporation and is a co-founder of OnLume. R.R.Z., A.B.S., E.L.R., J.M.W. and J.S.K. declare no competing interests.

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Real-time optical tumour detection

Real-time optical tumour detection performed under near-infrared (NIR) conditions (Fluobeam-800, Fluoptics, Grenoble, France) after intravenous administration of CLR1502 (Cellectar Biosciences, Madison, Wisconsin, USA), a tumour-targeted NIR fluorophore, to a TRAMP mouse with spontaneous prostate tumours. Upon excision, multiple tumours were easily distinguishable within the seminal vesicle complex. (MP4 2803 kb)

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Zhang, R., Schroeder, A., Grudzinski, J. et al. Beyond the margins: real-time detection of cancer using targeted fluorophores. Nat Rev Clin Oncol 14, 347–364 (2017). https://doi.org/10.1038/nrclinonc.2016.212

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