Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Carbon nanotubes as photoacoustic molecular imaging agents in living mice

Nature Nanotechnology volume 3, pages 557–562 (2008)Cite this article

Abstract

Photoacoustic imaging of living subjects offers higher spatial resolution and allows deeper tissues to be imaged compared with most optical imaging techniques1,2,3,4,5,6,7. As many diseases do not exhibit a natural photoacoustic contrast, especially in their early stages, it is necessary to administer a photoacoustic contrast agent. A number of contrast agents for photoacoustic imaging have been suggested previously8,9,10,11,12,13,14,15, but most were not shown to target a diseased site in living subjects. Here we show that single-walled carbon nanotubes conjugated with cyclic Arg-Gly-Asp (RGD) peptides can be used as a contrast agent for photoacoustic imaging of tumours. Intravenous administration of these targeted nanotubes to mice bearing tumours showed eight times greater photoacoustic signal in the tumour than mice injected with non-targeted nanotubes. These results were verified ex vivo using Raman microscopy. Photoacoustic imaging of targeted single-walled carbon nanotubes may contribute to non-invasive cancer imaging and monitoring of nanotherapeutics in living subjects16.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Characterization of the photoacoustic properties of single-walled carbon nanotubes.
Figure 2: Photoacoustic detection of single-walled carbon nanotubes in living mice.
Figure 3: Single-walled carbon nanotube targets tumour in living mice.
Figure 4: Validation of the in vivo photoacoustic images by Raman ex vivo microscopy.
Figure 5: Comparison between photoacoustic imaging using single-walled carbon nanotubes and fluorescence imaging using quantum dots.

Similar content being viewed by others

References

  1. Xu, M. H. & Wang, L. H. V. Photoacoustic imaging in biomedicine. Rev. Sci. Instrum. 77, 041101 (2006).

    Article  Google Scholar 

  2. Oh, J. T. et al. Three-dimensional imaging of skin melanoma in vivo by dual-wavelength photoacoustic microscopy. J. Biomed. Opt. 11, 34032 (2006).

    Article  Google Scholar 

  3. Zhang, H. F., Maslov, K., Stoica, G. & Wang, L. V. Imaging acute thermal burns by photoacoustic microscopy. J. Biomed. Opt. 11, 054033 (2006).

    Article  Google Scholar 

  4. Wang, X., Xie, X., Ku, G., Wang, L. V. & Stoica, G. Noninvasive imaging of haemoglobin concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography. J. Biomed. Opt. 11, 024015 (2006).

    Article  Google Scholar 

  5. Zhang, H. F., Maslov, K., Stoica, G. & Wang, L. V. Functional photoacoustic microscopy for high-resolution and noninvasive in vivo imaging. Nat. Biotechnol. 24, 848–851 (2006).

    Article  CAS  Google Scholar 

  6. Manohar, S. et al. Initial results of in vivo non-invasive cancer imaging in the human breast using near-infrared photoacoustics. Opt. Express 15, 12277–12285 (2007).

    Article  Google Scholar 

  7. Ermilov, S. et al. Detection and noninvasive diagnostics of breast cancer with 2-colour laser optoacoustic imaging system. Proc. SPIE 6437, 643703 (2007).

    Article  Google Scholar 

  8. Eghtedari, M. et al. High sensitivity of in vivo detection of gold nanorods using a laser optoacoustic imaging system. Nano Lett. 7, 1914–1918 (2007).

    Article  CAS  Google Scholar 

  9. Li, P. C. et al. Photoacoustic imaging of multiple targets using gold nanorods. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 54, 1642–1647 (2007).

    Article  Google Scholar 

  10. Kim, G. et al. Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging. J. Biomed. Opt. 12, 044020 (2007).

    Article  Google Scholar 

  11. Yang, X., Skrabalak, S. E., Li, Z. Y., Xia, Y. & Wang, L. V. Photoacoustic tomography of a rat cerebral cortex in vivo with Au nanocages as an optical contrast agent. Nano Lett. 7, 3798–3802 (2007).

    Article  CAS  Google Scholar 

  12. Zharov, V. P. et al. Photoacoustic flow cytometry: principle and application for real-time detection of circulating single nanoparticles, pathogens and contrast dyes in vivo. J. Biomed. Opt. 12, 051503 (2007).

    Article  Google Scholar 

  13. Li, M.-L. et al. Simultaneous molecular and hypoxia imaging of brain tumours in vivo using spectroscopic photoacoustic tomography. Proc. IEEE 96, 481–489 (2008).

    Article  CAS  Google Scholar 

  14. Wei, C.-W. et al. In vivo photoacoustic imaging with multiple selective targeting using bioconjugated gold nanorods. Proc. SPIE 6856, 68560J (2008).

    Article  Google Scholar 

  15. Kim, K. et al. In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent. Proc. SPIE 6856, 68560H (2008).

    Article  Google Scholar 

  16. Bianco, A., Kostarelos, K. & Prato, M. Applications of carbon nanotubes in drug delivery. Curr. Opin. Chem. Biol. 9, 674–679 (2005).

    Article  CAS  Google Scholar 

  17. Liu, Z. et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nature Nanotech. 2, 47–52 (2007).

    Article  CAS  Google Scholar 

  18. Mizejewski, G. J. Role of integrins in cancer: survey of expression patterns. Proc. Soc. Exp. Biol. Med. 222, 124–138 (1999).

    Article  CAS  Google Scholar 

  19. Janssen, M. L. et al. Tumour targeting with radiolabelled alpha(v)beta(3) integrin binding peptides in a nude mouse model. Cancer Res. 62, 6146–6151 (2002).

    CAS  Google Scholar 

  20. Vaithilingam, S. et al. Ultrasonics Symposium, 2007, 2413–2416 (2007).

  21. Weissleder, R. & Ntziachristos, V. Shedding light onto live molecular targets. Nature Med. 9, 123–128 (2003).

    Article  CAS  Google Scholar 

  22. Keren, S., Gheysens, O., Levin, C. S. & Gambhir, S. S. A comparison between a time domain and continuous wave small animal optical imaging system. IEEE Trans. Med. Imaging 27, 58–63 (2008).

    Article  CAS  Google Scholar 

  23. Cai, W. et al. Peptide-labelled near-infrared quantum dots for imaging tumour vasculature in living subjects. Nano Lett. 6, 669–676 (2006).

    Article  CAS  Google Scholar 

  24. Schipper, M. L. et al. A pilot toxicology study of single-walled carbon nanotubes in a small sample of mice. Nature Nanotech. 3, 216–221 (2008).

    Article  CAS  Google Scholar 

  25. Kam, N. W., O'Connell, M., Wisdom, J. A. & Dai, H. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proc. Natl Acad. Sci. USA 102, 11600–11605 (2005).

    Article  CAS  Google Scholar 

  26. American National Standards Institute. American national standard for the safe use of lasers. ANSI Standard Z136.1–2000 (ANSI, New York, 2000).

  27. Loening, A. M. & Gambhir, S. S. AMIDE: a free software tool for multimodality medical image analysis. Mol. Imaging 2, 131–137 (2003).

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank J. Rosenberg for the statistical analysis. This work was supported, in part, by National Cancer Institute (NCI) Center for Cancer Nanotechnology Excellence (CCNE) U54 (to S.S.G.) and NCI In-Vivo Cancer Molecular Imaging Center (ICMIC) P50 CA114747 (to S.S.G.).

Author information

Authors and Affiliations

  1. Department of Radiology and Bio-X Program, Molecular Imaging Program at Stanford, Stanford University, Palo Alto, 94305, California, USA

    Adam De La Zerda, Cristina Zavaleta, Shay Keren, Sunil Bodapati, Jelena Levi, Bryan R. Smith, Zhen Cheng, Xiaoyuan Chen & Sanjiv S. Gambhir

  2. Department of Electrical Engineering, Stanford University, Palo Alto, 94305, California, USA

    Adam De La Zerda, Srikant Vaithilingam, Te-Jen Ma, Omer Oralkan & Butrus T. Khuri-Yakub

  3. Department of Chemistry, Stanford University, Palo Alto, 94305, California, USA

    Zhuang Liu & Hongjie Dai

  4. Department of Bioengineering, Stanford University, Palo Alto, 94305, California, USA

    Sanjiv S. Gambhir

Authors
  1. Adam De La Zerda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Zavaleta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shay Keren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Srikant Vaithilingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sunil Bodapati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhuang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jelena Levi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bryan R. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Te-Jen Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Omer Oralkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhen Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaoyuan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hongjie Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Butrus T. Khuri-Yakub
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sanjiv S. Gambhir
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.D. built the photoacoustic instrument, designed and performed the experiments and wrote the paper. C.Z. designed, performed and analysed the Raman experiments. S.K. built the photoacoustic instrument and designed the experiments. S.V. designed and built the photoacoustic instrument. S.B. performed the experiments and helped write the paper. Z.L. synthesized the single-walled carbon nanotube conjugates. J.L. performed the cell uptake studies. B.R.S. helped write the paper. T.M. and O.O. helped design the photoacoustic instrument. Z.C. helped perform the comparison to fluorescence imaging. X.C. provided the RGD peptides, performed the fluorescence imaging of QD-RGD conjugates and helped write the manuscript. H.D. was responsible for single-walled carbon nanotube conjugation synthesis. B.T.K. was responsible for building the photoacoustic instrument. S.S.G. was responsible for experimental design and wrote the paper.

Corresponding author

Correspondence to Sanjiv S. Gambhir.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

De La Zerda, A., Zavaleta, C., Keren, S. et al. Carbon nanotubes as photoacoustic molecular imaging agents in living mice. Nature Nanotech 3, 557–562 (2008). https://doi.org/10.1038/nnano.2008.231

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2008.231

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing