In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells

Abstract

The spread of cancer cells between organs, a process known as metastasis, is the cause of most cancer deaths1,2. Detecting circulating tumour cells—a common marker for the development of metastasis3,4—is difficult because ex vivo methods are not sensitive enough owing to limited blood sample volume and in vivo diagnosis is time-consuming as large volumes of blood must be analysed5,6,7. Here, we show a way to magnetically capture circulating tumour cells in the bloodstream of mice followed by rapid photoacoustic detection. Magnetic nanoparticles, which were functionalized to target a receptor commonly found in breast cancer cells, bound and captured circulating tumour cells under a magnet. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. By integrating in vivo multiplex targeting, magnetic enrichment, signal amplification and multicolour recognition, our approach allows circulating tumour cells to be concentrated from a large volume of blood in the vessels of tumour-bearing mice, and this could have potential for the early diagnosis of cancer and the prevention of metastasis in humans.

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Figure 1: In vivo magnetic enrichment using two-colour photoacoustic detection of CTCs.
Figure 2: In vitro measurement under stationary conditions.
Figure 3: In vitro measurement under flow conditions.
Figure 4: In vivo measurements of nanoparticles and cells mimicking CTCs.
Figure 5: Photoacoustic detection and magnetic enrichment of CTCs in tumour-bearing mice.

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Acknowledgements

This work is supported in part by National Institute of Health grant numbers R01EB000873, R01CA131164, R01 EB009230, R21EB0005123 and R21CA139373 (V.P.Z.), National Cancer Institute grant number CA133722 (L.Y.), National Science Foundation grant numbers DBI-0852737 (V.P.Z.) and CMMI-0709121 (J.-W.K.) and the Arkansas Biosciences Institute (J.-W.K. and V.P.Z.). The authors would like to thank Y.A. Wang of Ocean Nanotech, LLC, for providing MNPs, H.-M. Moon for his assistance with GNT synthesis, J. Daniels for cell culturing, Z. Cao for bioconjugation of MNPs and cell labelling, H.K. Sajja for production of human amino-terminal fragments of urokinase plasminogen activator, H. Mao for magnetic resonance imaging and S. Fergusson for his assistance with laser measurements.

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E.I.G. and V.P.Z. conceived and designed the experiments. J.-W.K was responsible for GNT synthesis and their characterization and bioconjugation, L.Y. for conjugation and characterization of MNPs, T.K. for providing assessments of cancer cells and E.I.G. and E.V.S. for the remaining experiments. All authors discussed the results. V.P.Z., E.I.G. and J.-W.K. co-wrote the paper with editorial comments from L.Y. and T.K.

Corresponding author

Correspondence to Vladimir P. Zharov.

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Galanzha, E., Shashkov, E., Kelly, T. et al. In vivo magnetic enrichment and multiplex photoacoustic detection of circulating tumour cells. Nature Nanotech 4, 855–860 (2009). https://doi.org/10.1038/nnano.2009.333

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