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Detection of cancer biomarkers in serum using a hybrid mechanical and optoplasmonic nanosensor

Nature Nanotechnology volume 9, pages 1047–1053 (2014)Cite this article

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Abstract

Blood contains a range of protein biomarkers that could be used in the early detection of disease. To achieve this, however, requires sensors capable of detecting (with high reproducibility) biomarkers at concentrations one million times lower than the concentration of the other blood proteins. Here, we show that a sandwich assay that combines mechanical and optoplasmonic transduction can detect cancer biomarkers in serum at ultralow concentrations. A biomarker is first recognized by a surface-anchored antibody and then by an antibody in solution that identifies a free region of the captured biomarker. This second antibody is tethered to a gold nanoparticle that acts as a mass and plasmonic label; the two signatures are detected by means of a silicon cantilever that serves as a mechanical resonator for ‘weighing’ the mass of the captured nanoparticles and as an optical cavity that boosts the plasmonic signal from the nanoparticles. The capabilities of the approach are illustrated with two cancer biomarkers: the carcinoembryonic antigen and the prostate specific antigen, which are currently in clinical use for the diagnosis, monitoring and prognosis of colon and prostate cancer, respectively. A detection limit of 1 × 10−16 g ml−1 in serum is achieved with both biomarkers, which is at least seven orders of magnitude lower than that achieved in routine clinical practice. Moreover, the rate of false positives and false negatives at this concentration is extremely low, ∼10−4.

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Figure 1: Schematic representation of the sandwich assay on the cantilevers and the effect of the sandwich assay on the resonance frequency of the cantilever.
Figure 2: Nanoparticle plasmon resonance and optical cantilever cavity.
Figure 3: Nanomechanical detection of the CEA protein biomarker.
Figure 4: Plasmonic detection of the CEA protein biomarker on the cantilever optical microcavity.
Figure 5: Biomarker detection limit by an unsophisticated plasmonic readout in cantilevers and reliability of the optomechanoplasmonic device.
Figure 6: Fractal nanoparticle distribution after the sandwich detection assay.

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Acknowledgements

We acknowledge financial support from the Spanish Science Ministry (MINECO) through projects MAT2012-36197 and INMUNO-SWING ITP-2011-0821-010000, and from the European Research Council through Starting Grant NANOFORCELLS (ERC-StG-2011-278860). R.A. da Silva acknowledges financial support from the Brazilian Agency CNPq through grant 209693/2012-6. The authors thank J. M. de la Fuente and V. Grazu for their assistance with the biochemical functionalization protocols.

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Authors and Affiliations

  1. IMM-Instituto de Microelectrónica de Madrid (CNM-CSIC), Isaac Newton 8, PTM, E-28760 Tres Cantos, Madrid, Spain

    P. M. Kosaka, V. Pini, J. J. Ruz, R. A. da Silva, M. U. González, D. Ramos, M. Calleja & J. Tamayo

  2. Instituto de Química, Universidade de Sao Paulo, Av. Prof. Lineu Prestes 748, Sao Paulo, 05508-900, Brazil

    R. A. da Silva

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  1. P. M. Kosaka
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Contributions

P.M.K., J.T. and M.C. conceived and designed the work. P.M.K. and R.A.S. performed the bioassays. P.M.K. and V.P. carried out the mechanical and scattering detection. P.M.K., V.P. and J.T. developed the instrumentation for mechanical and plasmonics detection. P.M.K., M.U.G. and V.P. carried out spectral scattering measurements. D.R., V.P. and M.U.G. performed the spectra scattering modelling. V.P., J.J.R. and P.M.K. executed the SEM surface inspections and developed the software for the data treatment. J.T., P.M.K. and M.C. wrote the manuscript with inputs from all authors. All the authors analysed the data, discussed the results and commented on the manuscript.

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Correspondence to J. Tamayo.

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The authors declare no competing financial interests.

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Kosaka, P., Pini, V., Ruz, J. et al. Detection of cancer biomarkers in serum using a hybrid mechanical and optoplasmonic nanosensor. Nature Nanotech 9, 1047–1053 (2014). https://doi.org/10.1038/nnano.2014.250

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