Abstract
A solid tumor is an organ composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. A prerequisite to understanding tumor pathophysiology is the ability to distinguish and monitor each component in dynamic studies. Standard fluorophores hamper simultaneous intravital imaging of these components. Here, we used multiphoton microscopy techniques and transgenic mice that expressed green fluorescent protein, and combined them with the use of quantum dot preparations. We show that these fluorescent semiconductor nanocrystals can be customized to concurrently image and differentiate tumor vessels from both the perivascular cells and the matrix. Moreover, we used them to measure the ability of particles of different sizes to access the tumor. Finally, we successfully monitored the recruitment of quantum dot–labeled bone marrow–derived precursor cells to the tumor vasculature. These examples show the versatility of quantum dots for studying tumor pathophysiology and creating avenues for treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jain, R.K., Munn, L.L. & Fukumura, D. Dissecting tumour pathophysiology using intravital microscopy. Nat. Rev. Cancer 2, 266–276 (2002).
Brown, E.B. et al. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat. Med. 7, 864–868 (2001).
Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715–725 (1998).
Zipfel, W.R., Williams, R.M. & Webb, W.W. Nonlinear magic: multiphoton microscopy in the biosciences. Nat. Biotechnol. 21, 1369–1377 (2003).
Brown, E. et al. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 9, 796–800 (2003).
Murray, C.B., Norris, D.J. & Bawendi, M.G. Synthesis and characterization of nearly monodisperse CdE (E = S, Se, Te) semiconductor nanocrystallites. J. Am. Chem. Soc. 115, 8706–8715 (1993).
Larson, D.R. et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo . Science 300, 1434–1436 (2003).
Wu, X. et al. Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat. Biotechnol. 21, 41–46 (2003).
Gao, X., Cui, Y., Levenson, R.M., Chung, L.W. & Nie, S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22, 969–976 (2004).
Jain, R.K. & Stroh, M. Zooming in and out with quantum dots. Nat. Biotechnol. 22, 959–960 (2004).
Steckel, J.S. et al. Blue luminescence from (CdS)ZnS core-shell nanocrystals. Angewandte Chemie-International Edition 43, 2154–2158 (2004).
Fisher, B.R., Eisler, H.J., Stott, N.E. & Bawendi, M.G. Emission intensity dependence and single-exponential behavior in single colloidal quantum dot fluorescence lifetimes. J. Phys. Chem. B 108, 143–148 (2004).
Pluen, A., Netti, P.A., Jain, R.K. & Berk, D.A. Diffusion of macromolecules in agarose gels: Comparison of linear and globular configurations. Biophys. J. 77, 542–552 (1999).
Dubertret, B. et al. In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 298, 1759–1762 (2002).
Hobbs, S.K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95, 4607–4612 (1998).
Chan, Y.T. et al. Incorporation of luminescent nanocrystals into monodisperse core-shell silica microspheres. Adv. Mater. 16, 2092–2097 (2004).
Carmeliet, P. & Jain, R.K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).
Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat. Rev. Cancer 2, 826–835 (2002).
Jain, R.K. & Duda, D.G. Role of bone marrow-derived cells in tumor angiogenesis and treatment. Cancer Cell 3, 515–516 (2003).
Bestvater, F. et al. Two-photon fluorescence absorption and emission spectra of dyes relevant for cell imaging. J. Microsc. 208, 108–115 (2002).
Torchilin, V.P., Rammohan, R., Weissig, V. & Levchenko, T.S. TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. Proc. Natl. Acad. Sci. USA 98, 8786–8791 (2001).
Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nat. Biotechnol. 18, 410–414 (2000).
Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287, 1804–1808 (2000).
Koike, N. et al. Tissue engineering: creation of long-lasting blood vessels. Nature 428, 138–139 (2004).
Jaiswal, J.K., Mattoussi, H., Mauro, J.M. & Simon, S.M. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat. Biotechnol. 21, 47–51 (2003).
Hines, M.A. & Guyot-Sionnest, P. Synthesis and characterization of strongly luminescing ZnS-Capped CdSe nanocrystals. J. Phys. Chem. 100, 468–471 (1996).
Dabbousi, B.O. et al. (CdSe)ZnS core-shell quantum dots: synthesis and characterization of a size series of highly luminescent nanocrystallites. J. Phys. Chem. B 101, 9463–9475 (1997).
Leunig, M. et al. Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice. Cancer Res. 52, 6553–6560 (1992).
Yuan, F. et al. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res. 54, 4564–4568 (1994).
Melder, R.J., Salehi, H.A. & Jain, R.K. Interaction of activated natural killer cells with normal and tumor vessels in cranial windows in mice. Microvasc. Res. 50, 35–44 (1995).
Acknowledgements
We thank J. Kahn and S. Roberge for their assistance with the animal preparations. We wish to acknowledge Y.T. Chan, P. Snee, J.S. Steckel and J.B. Tracy for their help with quantum dot synthesis, and R.J. Klein for the separation of bone marrow lineage-negative cells. This work was supported by a National Cancer Institute fellowship to M.S. (F32 CA103386), a US National Institutes of Health grant (5RO1 EB001961-06) to V.T., and a Bioengineering Research Partnership Grant (R24CA85140) and Program Project Grant (P01CA80124) to R.K.J. and D.F. This work was also supported by grants to M.G.B. from the National Science Foundation (NSF-CHE-020989) and the Army Research Office through the Institute for Collaborative Biotechnologies. D.G.D. is a Cancer Research Institute fellow.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Quantum dot micelle preparation did not accumulate in extravascular space. (PDF 240 kb)
Supplementary Movie 1
Vessel enhancement using fluorescence-labeled dextran 2,000,000 MW infusion. (AVI 968 kb)
Supplementary Movie 2
Vessel enhancement using quantum dot infusion. (AVI 1806 kb)
Supplementary Movie 3
Ex vivo quantum dot labeling of cells. (AVI 5579 kb)
Rights and permissions
About this article
Cite this article
Stroh, M., Zimmer, J., Duda, D. et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat Med 11, 678–682 (2005). https://doi.org/10.1038/nm1247
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1247
This article is cited by
-
Towards clinically translatable in vivo nanodiagnostics
Nature Reviews Materials (2017)
-
A Novel Fluorescent Quantum Dot Probe for the Rapid Diagnostic High Contrast Imaging of Tumor in Mice
Journal of Fluorescence (2017)
-
Cadmium-containing quantum dots: properties, applications, and toxicity
Applied Microbiology and Biotechnology (2017)
-
Next-generation in vivo optical imaging with short-wave infrared quantum dots
Nature Biomedical Engineering (2017)
-
Wide-field three-photon excitation in biological samples
Light: Science & Applications (2016)