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Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery

Nature Nanotechnology volume 9, pages 481–487 (2014)Cite this article

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Abstract

In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using ‘bulk’ imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.

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Figure 1: SWNT uptake into circulating cells.
Figure 2: Flow cytometry plots showing selective uptake of SWNTs into a blood monocyte subset.
Figure 3: SWNT-laden monocytes enter the tumour interstitium in a peptide-dependent manner.

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Acknowledgements

This work was supported by a number of grants. B.R.S. was supported by a National Institutes of Health (NIH) 25T post-doctoral training grant and is currently supported by a K99/R00 award (K99 CA160764). S.S.G. was supported by a Center for Cancer Nanotechnology Excellence–Translation (CCNE-T)-grant (National Cancer Institute U54 CA119367) and in vivo cellular and molecular imaging (ICMIC) grant (P50 CA114747). The authors thank C. Ball for discussions related to this work. The authors acknowledge technical assistance in experiments and analysis from M. Philips, S. Tabakman, J. Rosenberg, S. Kusy, C. Nielsen, H. Dai, A-L. Koh, R. Sinclair, C. Zavaleta, J. Strommer and CytoViva.

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Author notes

  1. Jennifer A. Prescher

    Present address: Present address: Department of Chemistry, University of California, Irvine, Irvine, California 92697, USA,

Authors and Affiliations

  1. Molecular Imaging Program at Stanford, The James H Clark Center, Stanford University, Stanford, 94305, California, USA

    Bryan Ronain Smith, Harikrishna Rallapalli, Jennifer A. Prescher, Timothy Larson & Sanjiv Sam Gambhir

  2. Department of Radiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Bryan Ronain Smith, Timothy Larson & Sanjiv Sam Gambhir

  3. Department of Genetics, Stanford University School of Medicine, Stanford, 94305, California, USA

    Eliver Eid Bou Ghosn & Leonore A. Herzenberg

  4. Department of Bioengineering and Department of Materials Science & Engineering, Stanford University, Stanford, 94305, California, USA

    Sanjiv Sam Gambhir

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Contributions

B.R.S. and S.S.G. conceived and designed the experiments. B.R.S. performed the experiments and contributed materials and analysis tools. B.R.S. and S.S.G. analysed the data and wrote the manuscript. E.E.B.G. designed, performed and analysed 12-colour, 14-parameter FACS for immune cell analysis of blood samples, discussed results, contributed reagents, and commented on the manuscript. L.A.H. provided guidance and assisted with analysis regarding high-dimensional flow cytometry and contributed materials and analysis tools. H.R. assisted with analyses of intravital imaging experiments. B.R.S. and J.A.P. designed, performed and analysed initial flow cytometry assays. T.L. assisted with characterization of nanotubes.

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Correspondence to Bryan Ronain Smith or Sanjiv Sam Gambhir.

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Smith, B., Ghosn, E., Rallapalli, H. et al. Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery. Nature Nanotech 9, 481–487 (2014). https://doi.org/10.1038/nnano.2014.62

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