Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy

Abstract

Metastasis is an impediment to the development of effective cancer therapies. Our understanding of metastasis is limited by our inability to follow this process in vivo. Fluorescence microscopy offers the potential to follow cells at high resolution in living animals. Semiconductor nanocrystals, quantum dots (QDs), offer considerable advantages over organic fluorophores for this purpose. We used QDs and emission spectrum scanning multiphoton microscopy to develop a means to study extravasation in vivo. Although QD labeling shows no deleterious effects on cultured cells, concern over their potential toxicity in vivo has caused resistance toward their application to such studies. To test if effects of QD labeling emerge in vivo, tumor cells labeled with QDs were intravenously injected into mice and followed as they extravasated into lung tissue. The behavior of QD-labeled tumor cells in vivo was indistinguishable from that of unlabeled cells. QDs and spectral imaging allowed the simultaneous identification of five different populations of cells using multiphoton laser excitation. Besides establishing the safety of QDs for in vivo studies, our approach permits the study of multicellular interactions in vivo.

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Figure 1: Intracellular labeling of tumor cells by QDs permits in vivo imaging despite tissue autofluorescence.
Figure 2: QDs can be used to study the distribution of tumor cells in organs and tissues.
Figure 3: QD labeling has no effect on extravasation and tumor formation compared with unlabeled cells.
Figure 4: QDs allow the simultaneous tracking of different populations of cells in lung tissue.
Figure 5: Emission-scanning multiphoton microscopy can identify at least five populations of cells.

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Acknowledgements

This work was supported by the Cancer Research Institute (E.B.V.), the American Cancer Society (RPG-98-177-01-CDD, S.M.S.) and the National Science Foundation (NSF BES-0119468, S.M.S.). H.M. acknowledges K. Ward and A. Ervin at the Office of the Naval Research for research support (ONR N001400WX20094). The views, opinions and findings described in this report are those of the authors and should not be construed as official Department of the Navy positions, policies or decisions. The authors wish to thank A. North and the Bio-Imaging Resource Center of Rockefeller University and B. Sanchez from the Rockefeller University Laboratory Animal Resource Center, for excellent support.

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Correspondence to Sanford M Simon.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Quantum dots can be seen over tissue background. (PDF 105 kb)

Supplementary Fig. 2

Emission spectra of DHLA-capped QDs is not affected by aldehyde fixation. (PDF 254 kb)

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Voura, E., Jaiswal, J., Mattoussi, H. et al. Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat Med 10, 993–998 (2004). https://doi.org/10.1038/nm1096

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