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.

Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets

Nature Nanotechnology volume 8, pages 735–741 (2013)Cite this article

Subjects

An Erratum to this article was published on 07 November 2013

This article has been updated

Abstract

The spread of cancer throughout the body is driven by circulating tumour cells (CTCs)1. These cells detach from the primary tumour and move from the bloodstream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods for measuring and studying these cells in patient blood samples prevents the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs2,3. However, the devices are reliant on three-dimensional structures, which limits further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolating CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalized graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at a low concentration of target cells (73 ± 32.4% at 3–5 cells per ml blood).

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Graphene oxide chip and functionalization/characterization of graphene oxide.
Figure 2: Characterization of the graphene oxide chip with cells in buffer solution.
Figure 3: Characterization of the graphene oxide chip with MCF-7 cells spiked into whole blood.
Figure 4: Fluorescence microscope images and quantification of CTCs captured from cancer patient samples.

Change history

  • 01 October 2013

    In the version of this Letter originally published, in Fig. 1b one of the PEG chains was misplaced. This has now been corrected in the HTML and PDF versions.

References

  1. Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. New Engl. J Med. 351, 781–791 (2004).

    Article  CAS  Google Scholar 

  2. Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).

    Article  CAS  Google Scholar 

  3. Maheswaran, S. et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377 (2008).

    Article  CAS  Google Scholar 

  4. Willipinski-Stapelfeldt, B. et al. Changes in cytoskeletal protein composition indicative of an epithelial–mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin. Cancer Res. 11, 8006–8014 (2005).

    Article  CAS  Google Scholar 

  5. Bednarz-Knoll, N., Alix-Panabières, C. & Pantel, K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 31, 673–687 (2012).

    Article  CAS  Google Scholar 

  6. Pantel, K., Brakenhoff, R. H. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nature Rev. Cancer 8, 329–340 (2008).

    Article  CAS  Google Scholar 

  7. Lin, H. K. et al. Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin. Cancer Res. 16, 5011–5018 (2010).

    Article  CAS  Google Scholar 

  8. Dobrovolskaia, M. A. & McNeil, S. E. Immunological properties of engineered nanomaterials. Nature Nanotech. 2, 469–478 (2007).

    Article  CAS  Google Scholar 

  9. Xia, X-R., Monteiro-Riviere, N. A. & Riviere, J. E. An index for characterization of nanomaterials in biological systems. Nature Nanotech. 5, 671–675 (2010).

    Article  CAS  Google Scholar 

  10. Wang, S. et al. Three-dimensional nanostructured substrates toward efficient capture of circulating tumor cells. Angew. Chem. Int. Ed. 121, 9132–9135 (2009).

    Article  Google Scholar 

  11. Lee, S-K. et al. Nanowire substrate-based laser scanning cytometry for quantitation of circulating tumor cells. Nano Lett. 12, 2697–2704 (2012).

    Article  CAS  Google Scholar 

  12. Zhang, N. et al. Electrospun TiO2 nanofiber-based cell capture assay for detecting circulating tumor cells from colorectal and gastric cancer patients. Adv. Mater. 24, 2756–2760 (2012).

    Article  CAS  Google Scholar 

  13. Liu, Z., Robinson, J. T., Sun, X. & Dai, H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J. Am. Chem. Soc. 130, 10876–10877 (2008).

    Article  CAS  Google Scholar 

  14. Mohanty, N. & Berry, V. Graphene-based single-bacterium resolution biodevice and DNA transistor: interfacing graphene derivatives with nanoscale and microscale biocomponents. Nano Lett. 8, 4469–4476 (2008).

    Article  CAS  Google Scholar 

  15. Ramanathan, T. et al. Functionalized graphene sheets for polymer nanocomposites. Nature Nanotech. 3, 327–331 (2008).

    Article  CAS  Google Scholar 

  16. Dreyer, D. R., Park, S., Bielawski, C. W. & Ruoff, R. S. The chemistry of graphene oxide. Chem. Soc. Rev. 39, 228–240 (2010).

    Article  CAS  Google Scholar 

  17. Sun, X. et al. Nano-graphene oxide for cellular imaging and drug delivery. Nano Res. 1, 203–212 (2008).

    Article  CAS  Google Scholar 

  18. Eda, G., Fanchini, G. & Chhowalla, M. Large-area ultrathin films of reduced graphene oxide as a transparent and flexible electronic material. Nature Nanotech. 3, 270–274 (2008).

    Article  CAS  Google Scholar 

  19. Li, X. et al. Highly conducting graphene sheets and Langmuir–Blodgett films. Nature Nanotech. 3, 538–542 (2008).

    Article  CAS  Google Scholar 

  20. Wang, H., Wang, X., Li, X. & Dai, H. Chemical self-assembly of graphene sheets. Nano Res. 2, 336–342 (2009).

    Article  CAS  Google Scholar 

  21. Sieuwerts, A. M. et al. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J. Natl Cancer Inst. 101, 61–66 (2009).

    Article  CAS  Google Scholar 

  22. Salic, A. & Mitchison, T. J. A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc. Natl Acad. Sci. USA 105, 2415–2420 (2008).

    Article  CAS  Google Scholar 

  23. Lustberg, M., Jatana, K. R., Zborowski, M. & Chalmers, J. J. Emerging technologies for CTC detection based on depletion of normal cells. Recent Results Cancer Res. 195, 97–110 (2012).

    Article  Google Scholar 

  24. Stott, S. L. et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc. Natl Acad. Sci. USA 107, 18392–18397 (2010).

    Article  CAS  Google Scholar 

  25. Mego, M. et al. Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells. Int. J. Cancer 129, 417–423 (2011).

    Article  CAS  Google Scholar 

  26. Alix-Panabières, C., Schwarzenbach, H. & Pantel, K. Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med. 63, 199–215 (2012).

    Article  Google Scholar 

  27. Ozkumur, E. et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci. Transl. Med. 5, 179ra147 (2013).

    Article  Google Scholar 

  28. Krebs, M. G. et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J. Thorac. Oncol. 7, 306–315 (2012).

    Article  Google Scholar 

  29. Edgerton, S. M., Moore, D. II, Merkel, D. & Thor, A. D. erbB-2 (HER-2) and breast cancer progression. Appl. Immunohistochem. Mol. Morphol. 11, 214–221 (2003).

    Article  CAS  Google Scholar 

  30. Amir, E. et al. Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies. Cancer Treat. Rev. 38, 708–714 (2012).

    Article  Google Scholar 

  31. Fehm, T. et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res. Treat. 124, 403–412 (2010).

    Article  CAS  Google Scholar 

  32. Riethdorf, S. et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin. Cancer Res. 16, 2634–2645 (2010).

    Article  CAS  Google Scholar 

  33. Pestrin, M. et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-agent Lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res. Treat. 134, 283–289 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank K. Herman and S. Laurinec for procurement of patient blood samples, and S. Fouladdel for technical help with qRT-PCR. This work was supported by the National Institutes of Health (NIH) Director's New Innovator Award (1DP2OD006672-01), a Career Development Program of the Gastrointestinal Specialized Program of Research Excellence (GI SPORE) award (CA130810), and a 3M non-tenured Faculty Award. The work was performed in part at the Lurie Nanofabrication Facility, a member of the National Nanotechnology Infrastructure Network, which is supported by the National Science Foundation.

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Hyeun Joong Yoon, Tae Hyun Kim, Zhuo Zhang, Trinh M. Pham & Sunitha Nagrath

  2. Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Tae Hyun Kim

  3. Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Ebrahim Azizi, Costanza Paoletti, Nithya Ramnath, Max S. Wicha & Daniel F. Hayes

  4. Department of Surgery, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Jules Lin & Diane M. Simeone

  5. Translational Oncology Program, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Max S. Wicha, Diane M. Simeone & Sunitha Nagrath

Authors
  1. Hyeun Joong Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tae Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhuo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ebrahim Azizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Trinh M. Pham
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Costanza Paoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jules Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nithya Ramnath
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Max S. Wicha
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel F. Hayes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Diane M. Simeone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sunitha Nagrath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.Y. and S.N. conceived and designed the study. H.Y. and T.K. fabricated devices and performed the experiments. T.K., Z.Z. and T.P. performed the cell culture. E.A. analysed the RNA data. C.P., J.L., N.R., M.W., D.H. and D.S. prepared the clinical samples. H.Y. and S.N. analysed the data and co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Sunitha Nagrath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Information (PDF 15968 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yoon, H., Kim, T., Zhang, Z. et al. Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Nature Nanotech 8, 735–741 (2013). https://doi.org/10.1038/nnano.2013.194

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2013.194

This article is cited by

Search

Advanced search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research