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A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging

Nature Biomedical Engineering volume 8, pages 1092–1108 (2024)Cite this article

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Abstract

The efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215—a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650–900 nm) and shortwave infrared (SWIR) fluorescence imaging (900–1,700 nm)—can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing. In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs. At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions.

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Fig. 1: CJ215 spectral, in vitro and in vivo assessment.
Fig. 2: Tumour resection using SWIRFI (>900 nm, sensor response) and CJ215.
Fig. 3: Extended spectral emission (>1,100, >1,300 nm) assessment of CJ215 via SWIRFI.
Fig. 4: NIRFI (745 nm excitation, 840 nm emission) necropsy biodistribution assessment of CJ215 in four tumour models.
Fig. 5: Necropsy and histological analysis of additional regions of interest during CT26 tumour resection.
Fig. 6: SWIRFI (>900 nm) and CJ215 enable contrast-based image generation for binary tumour delineation.
Fig. 7: CJ215 assessment in a colorectal peritoneal carcinomatosis model (SW1222).
Fig. 8: Non-invasive, non-contact and ambient-light-resistant wound monitoring through commercially available bandages via SWIRFI (>1,300 nm) and CJ215.

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Data availability

The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.

Code availability

The code required to generate the CNR images via framewise or pixelwise methods is included in the Supplementary Information. All code to process the images in ImageJ is readily available via plugins.

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Acknowledgements

We thank S. Urbain and F. Scherninski from Proimaging (Paris, France) along with J. Tran-Guyon and V. Guyon from Laboratoires Synth-Innove (Paris, France) for helpful advice, discussions and for providing CJ215 for this investigation (CJ215 was a gift from Proimaging which did not sponsor this research other than providing CJ215); the small-animal imaging core at MSKCC for assistance as well as RARC at MSKCC for advice on animal experiments and excellent animal assistance, especially A. Ritter and E. Soto-Lemus; N. Fan, B. Shrestha and W. Kang of the Molecular Cytology Core Facility at MSKCC and I. Miranda of the Laboratory of Comparative Pathology at MSKCC; E. Chan, E. Rosiek and Y. Romin of the Molecular Cytology core at MSKCC for microscopy assistance. Support for this work was provided by the the National Science Foundation CAREER Award (1752506, D.A.H.), the NCI (R01-CA-257811, J.G., R01-CA215719, D.A.H. and Cancer Center Support Grant P30-CA008748, Selwyn Vickers/MSKCC), NIBIB (R56 EB030512, J.G., R01-EB033651, D.A.H.; R00-EB033580, M.K.), the Department of Defense Congressionally Directed Medical Research Program (W81XWH-22-1-0563, D.A.H.), the Ara Parseghian Medical Research Fund (D.A.H.), the American Cancer Society Research Scholar Grant (GC230452, D.A.H.), the Louis and Rachel Rudin Foundation (D.A.H.), MSK’s Cycle for Survival’s Equinox Innovation Award in Rare Cancers (D.A.H.), the Experimental Therapeutics Center of MSKCC (D.A.H. and J.G.), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research (D.A.H.) and the Vince Lombardi Cancer Foundation (J.G.). This work was partially funded by Memorial Sloan Kettering Cancer Center’s Technology Development Funding Program, flexTDF (D.V.).

Author information

Author notes

  1. These authors contributed equally: Ali Yasin Sonay, Elana Apfelbaum.

Authors and Affiliations

  1. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Benedict Edward Mc Larney, Ali Yasin Sonay, Elana Apfelbaum, Nermin Mostafa, Dana Goerzen, Elizabeth Isaac, Ngan Bao Phung, Magdalena Skubal, Mijin Kim, Anuja Ogirala, Daniel A. Heller & Jan Grimm

  2. Pharmacology Program, Weill Cornell Medical College, New York, NY, USA

    Elana Apfelbaum, Christine Habjan, Elizabeth Isaac, Ngan Bao Phung, Daniel A. Heller & Jan Grimm

  3. Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY, USA

    Sébastien Monette

  4. Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Dana Goerzen & Daniel A. Heller

  5. Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nicole Aguirre

  6. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    Rüdiger M. Exner & Mijin Kim

  7. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Darren Veach & Jan Grimm

  8. Department of Radiology, Weill Cornell Medical Center, New York, NY, USA

    Darren Veach & Jan Grimm

  9. Molecular Imaging Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jan Grimm

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  1. Benedict Edward Mc Larney
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Contributions

B.E.M.L conceived, designed and performed the experiments, and designed the analysis pipelines and CNR code. A.Y.S. designed and performed Sta and zVAD experiments. E.A. designed and performed in vivo experiments. B.E.M.L. and C.H. performed in vitro assessment and microscopy. B.E.M.L., D.G. and M.K. performed spectral characterization. R.M.E. performed the in silico serum docking assessment. N.A. and D.V. generated and assisted with metastatic modelling. S.M. performed pathology analysis and staining. N.M., E.I., N.B.P. and M.S. generated various tumour models and performed experiments. A.O. and N.M. conducted in vivo experimental design and work. B.E.M.L., D.A.H. and J.G. designed experiments and supervised the study. All authors discussed the work, and edited and commented on the manuscript.

Corresponding author

Correspondence to Jan Grimm.

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Competing interests

D.A.H. is a co-founder with equity interest in Lime Therapeutics Inc., Selectin Therapeutics Inc., and Nine Diagnostics Inc.; is a member of the scientific advisory board of Concarlo Therapeutics Inc., Celine Therapeutics Inc., Nanorobotics Inc., and Mediphage Bioceuticals Inc.; and is a consultant for METiS Therapeutics Inc. B.M.L., D.A.H. and J.G. have filed a provisional patent in relation to some of the work in this paper. The other authors declare no competing interests.

Peer review

Peer review information

Nature Biomedical Engineering thanks Jianmin Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 In silico assessment of serum binding affinity of CJ215 and ICG to human serum albumin (HSA) and mouse serum albumin (MSA).

A) Overview of ALIGN results between human and murine serum albumin revealed a sequence homology of 72.37 %. B) Predicted aligned error for murine albumin (AF-P07724-F1). C) Left, overview of CJ215 docking pose with HSA. Right, zoomed in portion of docking site. D) Residue interactions of HSA with CJ215. E) Left, overview of ICG binding with HSA. Right, zoomed in view of the binding site. F) Residue interactions of HSA with ICG. G) Left, overview of docking pose of CJ215 with MSA. Right, zoomed in view of the binding site. H) Residue interactions of CJ215 with MSA. J) Left, overview of ICG binding with MSA. Right, zoomed in view of the binding site. K) Residue interactions of ICG and MSA. For D, F, H, & K the non-covalent binding co-efficient (GlideScore) is shown in italics, where more negative binding correlates to a stronger binding and interaction. In all cases CJ215 showed improved binding efficacy to albumin over ICG.

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Video 1 (download MP4 )

CJ215 uptake in single 4T1 cells.

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CJ215 uptake in 4T1 spheroids.

Video 3 (download MP4 )

SWIRFI CNR mode (pixel-based) of CJ215 uptake in various tumour models.

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SWIRFI CNR mode (pixel-based) of CJ215 uptake in wounds, without and with bandage application.

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Mc Larney, B.E., Sonay, A.Y., Apfelbaum, E. et al. A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging. Nat. Biomed. Eng 8, 1092–1108 (2024). https://doi.org/10.1038/s41551-024-01248-w

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