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In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes

Nature Nanotechnology volume 8, pages 873–880 (2013)Cite this article

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Abstract

Single-walled carbon nanotubes are particularly attractive for biomedical applications, because they exhibit a fluorescent signal in a spectral region where there is minimal interference from biological media. Although single-walled carbon nanotubes have been used as highly sensitive detectors for various compounds, their use as in vivo biomarkers requires the simultaneous optimization of various parameters, including biocompatibility, molecular recognition, high fluorescence quantum efficiency and signal transduction. Here we show that a polyethylene glycol ligated copolymer stabilizes near-infrared-fluorescent single-walled carbon nanotubes sensors in solution, enabling intravenous injection into mice and the selective detection of local nitric oxide concentration with a detection limit of 1 µM. The half-life for liver retention is 4 h, with sensors clearing the lungs within 2 h after injection, thus avoiding a dominant route of in vivo nanotoxicology. After localization within the liver, it is possible to follow the transient inflammation using nitric oxide as a marker and signalling molecule. To this end, we also report a spatial-spectral imaging algorithm to deconvolute fluorescence intensity and spatial information from measurements. Finally, we demonstrate that alginate-encapsulated single-walled carbon nanotubes can function as implantable inflammation sensors for nitric oxide detection, with no intrinsic immune reactivity or other adverse response for more than 400 days.

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Figure 1: Characterization and 2Dλ imaging analysis of DNA-wrapped SWNT complexes.
Figure 2: Effect of PEGylation for tail-vein-injected SWNTs.
Figure 3: Biodistribution and biocompatibility of PEG-(AAAT)7-SWNTs in 129 mice.
Figure 4: In vivo sensor quenching due to inflammation.
Figure 5: Additional sensor construct with broader in vivo localization possibilities and long-term sensing capabilities.

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Acknowledgements

This work was supported by the National Institutes of Health (T32 Training Grant in Environmental Toxicology ES007020, to N.I.), the National Cancer Institute (grant P01 CA26731), the National Institute of Environmental Health Sciences (grant P30 ES002109), a Beckman Young Investigator Award and a National Science Foundation Presidential Early Career Award for Scientists and Engineers (to M.S.S.), the TUBITAK 2211 and 2214 Research fellowship programme (F.S. and S.S.) and the METU-DPT-OYP programme (F.S. and S.S). A Biomedical Innovation grant from Sanofi Aventis to M.S.S. is also acknowledged. The authors thank T. Grusecki for assistance with the deconvolution code, as well as R. Langer, D. Anderson and P. Dedon for helpful discussions.

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Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Nicole M. Iverson, Paul W. Barone, Mia Shandell, Selda Sen, Fatih Sen, Thomas P. McNicholas, Nigel Reuel & Michael S. Strano

  2. Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Nicole M. Iverson, Laura J. Trudel, Vsevolod Ivanov, Esha Atolia, Edgardo Farias & Gerald N. Wogan

  3. Department of Chemistry, Middle East Technical University, Ankara, 06531, Turkey

    Selda Sen

  4. Department of Chemistry, Dumlupinar University, Kutahya, 43020, Turkey

    Fatih Sen

  5. Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Nicola M. A. Parry

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  1. Nicole M. Iverson
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Contributions

M.S.S. conceived of the original concept, with experimental design of in vivo experiments by G.W., M.S.S., N.I. and P.B. Sensor design and synthesis were performed by P.B., M.S., S.S., F.S., T.M., N.R. and N.I. N.I., L.T., M.S., V.I., E.A. and E.F. performed and analysed the in vivo studies. N.I., P.B., M.S., T.M. and N.R. optimized the animal imaging system. V.I. and N.I. designed the mathematical model and computer program to deconvolute the data. N.P. read and interpreted the histology slides. The manuscript was written by M.S.S and N.I. with contributions from G.W., P.B., L.T. and T.M.

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Correspondence to Michael S. Strano.

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Iverson, N., Barone, P., Shandell, M. et al. In vivo biosensing via tissue-localizable near-infrared-fluorescent single-walled carbon nanotubes. Nature Nanotech 8, 873–880 (2013). https://doi.org/10.1038/nnano.2013.222

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