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High-sensitivity imaging of time-domain near-infrared light transducer

Nature Photonics volume 13, pages 525–531 (2019)Cite this article

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An Author Correction to this article was published on 09 June 2021

A Publisher Correction to this article was published on 19 June 2019

This article has been updated

Abstract

The optically transparent biological window in the near-infrared (NIR) spectral range allows deep-tissue excitation and the detection of fluorescence signals1,2. Spectrum-domain discrimination of NIR contrast agents via an upconversion or downshifting scheme requires sufficient (anti-) Stokes shift to separate excitation and fluorescence emission. Here, we report a time-domain (τ) scheme in which about 5,000 ytterbium signal transducers are condensed within an optically inert and biocompatible CaF2 shell (2.3 nm), which forms a 14.5 nm τ-dot. Because of the long-lived and spectrally narrowly defined excited state of pure ytterbium ions, the NIR τ-dot can convert the NIR pulsed excitation into long-decaying luminescence with an efficiency approaching 100%. Within a safe injection dosage of 13 μg g−1, an excitation power density of 1.1 mW cm−2 was sufficient to image organs with a signal-to-noise ratio of >9. The high brightness of τ-dots further allows long-term in vivo passive targeting and dynamic tracking in a tumour-bearing mouse model.

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Fig. 1: Schematic illustration of the high brightness of time-domain optical transducers provided by luminescent τ-dot nanocrystals.
Fig. 2: Morphology characterization and luminescence intensity measurements of time-domain τ-dots, upconversion and downshifting nanocrystals.
Fig. 3: Comparison of the luminescence imaging performances of as-prepared NIR τ-dots, typical upconversion nanoparticles used in the NIR I region and downshifting nanoparticles used in the NIR II region that were injected in mice through the tail vein.
Fig. 4: Multiplexed time-resolved bioimaging of lifetime-tunable NaYbF4@CaF2 τ-dot nanocrystals.
Fig. 5: Comparison of performances in passive tumour-targeting experiments of α-NaYbF4@CaF2 NIR τ-dots in time-gated detection mode and c.w. mode and β-NaYbF4,2%Er,2%Ce@NaYF4 downshifting nanoparticles emitting around 1,550 nm.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

Change history

  • 19 June 2019

    In the version of this Letter originally published online, in the sentence beginning “Here, we report a time-domain (τ) scheme”, ‘>5,000 ytterbium signal transducers’ should have read ‘about 5,000 ytterbium signal transducers’. And in the graph labelled ‘Downshifting’ in Fig. 1d the red peak was labelled ‘Em.’; instead it should have been labelled ‘Ex.’ These errors have now been corrected in all versions.

  • 09 June 2021

    A Correction to this paper has been published: https://doi.org/10.1038/s41566-021-00834-7

References

  1. Frangioni, J. V. In vivo near-infrared fluorescence imaging. Curr. Opin. Chem. Biol. 7, 626–634 (2003).

    Article  Google Scholar 

  2. Smith, A. M., Mancini, M. C. & Nie, S. Bioimaging: second window for in vivo imaging. Nat. Nanotechnol. 4, 710–711 (2009).

    Article  ADS  Google Scholar 

  3. Nguyen, Q. T. & Tsien, R. Y. Fluorescence-guided surgery with live molecular navigation—a new cutting edge. Nat. Rev. Cancer 13, 653–662 (2013).

    Article  Google Scholar 

  4. Vahrmeijer, A. L., Hutteman, M., van der Vorst, J. R., van de Velde, C. J. H. & Frangioni, J. V. Image-guided cancer surgery using near-infrared fluorescence. Nat. Rev. Clin. Oncol. 10, 507–518 (2013).

    Article  Google Scholar 

  5. Medintz, I. L., Uyeda, H. T., Goldman, E. R. & Mattoussi, H. Quantum dot bioconjugates for imaging, labelling and sensing. Nat. Mater. 4, 435–446 (2005).

    Article  ADS  Google Scholar 

  6. Alivisatos, A. P. Semiconductor clusters, nanocrystals and quantum dots. Science 271, 933–937 (1996).

    Article  ADS  Google Scholar 

  7. Resch-Genger, U., Grabolle, M., Cavaliere-Jaricot, S., Nitschke, R. & Nann, T. Quantum dots versus organic dyes as fluorescent labels. Nat. Methods 5, 763–775 (2008).

    Article  Google Scholar 

  8. Bünzli, J. G. & Eliseeva, S. V. Lanthanide NIR luminescence for telecommunications, bioanalyses and solar energy conversion. J. Rare Earths 28, 824–842 (2010).

    Article  Google Scholar 

  9. Zhou, B., Shi, B., Jin, D. & Liu, X. Controlling upconversion nanocrystals for emerging applications. Nat. Nanotechnol. 10, 924–936 (2015).

    Article  ADS  Google Scholar 

  10. Auzel, F. Upconversion and anti-Stokes processes with f and d ions in solids. Chem. Rev. 104, 139–174 (2004).

    Article  Google Scholar 

  11. Zhou, J., Liu, Z. & Li, F. Upconversion nanophosphors for small-animal imaging. Chem. Soc. Rev. 41, 1323–1349 (2012).

    Article  Google Scholar 

  12. Naczynski, D. J. et al. Rare-earth-doped biological composites as in vivo shortwave infrared reporters. Nat. Commun. 4, 2199 (2013).

    Article  ADS  Google Scholar 

  13. Stouwdam, J. W. & Van Veggel, F. C. J. M. Near-infrared emission of redispersible Er3+, Nd3+ and Ho3+ doped LaF3 nanoparticles. Nano Lett. 2, 733–737 (2002).

    Article  ADS  Google Scholar 

  14. Boyer, J. C. & Van Veggel, F. C. J. M. Absolute quantum yield measurements of colloidal NaYF4: Er3+, Yb3+ upconverting nanoparticles. Nanoscale 2, 1417–1419 (2010).

    Article  ADS  Google Scholar 

  15. Wisser, M. D. et al. Enhancing quantum yield via local symmetry distortion in lanthanide-based upconverting nanoparticles. ACS Photonics 3, 1523–1530 (2016).

    Article  Google Scholar 

  16. Zhong, Y. et al. Boosting the down-shifting luminescence of rare-earth nanocrystals for biological imaging beyond 1,500 nm. Nat. Commun. 8, 737 (2017).

    Article  ADS  Google Scholar 

  17. Wang, F., Wang, J. & Liu, X. Direct evidence of a surface quenching effect on size-dependent luminescence of upconversion nanoparticles. Angew. Chem. Int. Ed. 49, 7456–7460 (2010).

    Article  Google Scholar 

  18. Wen, S. et al. Advances in highly doped upconversion nanoparticles. Nat. Commun. 9, 2415 (2018).

    Article  ADS  Google Scholar 

  19. Del Rosal, B. et al. Overcoming autofluorescence: long-lifetime infrared nanoparticles for time-gated in vivo imaging. Adv. Mater. 28, 10188–10193 (2016).

    Article  Google Scholar 

  20. Zheng, X. et al. High-contrast visualization of upconversion luminescence in mice using time-gating approach. Anal. Chem. 88, 3449–3454 (2016).

    Article  Google Scholar 

  21. Kobayashi, H., Ogawa, M., Alford, R., Choyke, P. L. & Urano, Y. New strategies for fluorescent probe design in medical diagnostic imaging. Chem. Rev. 110, 2620–2640 (2010).

    Article  Google Scholar 

  22. Wang, Y. et al. Rare-earth nanoparticles with enhanced upconversion emission and suppressed rare-earth-ion leakage. Chem. Eur. J. 18, 5558–5564 (2012).

    Article  Google Scholar 

  23. Ma, C. et al. Optimal sensitizer concentration in single upconversion nanocrystals. Nano Lett. 17, 2858–2864 (2017).

    Article  ADS  Google Scholar 

  24. Prosposito, P. et al. Femtosecond dynamics of IR molecules in hybrid materials. J. Lumin. 94-95, 641–644 (2001).

    Article  Google Scholar 

  25. Prosposito, P. et al. IR-luminescent molecules in hybrid materials. J. Solgel Sci. Technol. 26, 909–913 (2003).

    Article  Google Scholar 

  26. Casalboni, M., De Matteis, F., Prosposito, P., Quatela, A. & Sarcinelli, F. Fluorescence efficiency of four infrared polymethine dyes. Chem. Phys. Lett. 373, 372–378 (2003).

    Article  ADS  Google Scholar 

  27. Tao, Z. et al. Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm. Angew. Chem. Int. Ed. 52, 13002–13006 (2013).

    Article  Google Scholar 

  28. Semonin, O. E. et al. Absolute photoluminescence quantum yields of IR-26 dye, PbS and PbSe quantum dots. J. Phys. Chem. Lett. 1, 2445–2450 (2010).

    Article  Google Scholar 

  29. Greben, M., Fucikova, A. & Valenta, J. Photoluminescence quantum yield of PbS nanocrystals in colloidal suspensions. J. Appl. Phys. 117, 144306 (2015).

    Article  ADS  Google Scholar 

  30. Hinds, S. et al. NIR-emitting colloidal quantum dots having 26% luminescence quantum yield in buffer solution. J. Am. Chem. Soc. 129, 7218–7219 (2007).

    Article  Google Scholar 

  31. Kisler, K. et al. In vivo imaging and analysis of cerebrovascular hemodynamic responses and tissue oxygenation in the mouse brain. Nat. Protoc. 13, 1377–1402 (2018).

    Article  Google Scholar 

  32. Lu, Y. et al. Tunable lifetime multiplexing using luminescent nanocrystals. Nat. Photon. 8, 32–36 (2013).

    Article  ADS  Google Scholar 

  33. Fan, Y. et al. Lifetime-engineered NIR-II nanoparticles unlock multiplexed in vivo imaging. Nat. Nanotechnol. 13, 941–946 (2018).

    Article  ADS  Google Scholar 

  34. Ortgies, D. H. et al. Lifetime-encoded infrared-emitting nanoparticles for in vivo multiplexed imaging. ACS Nano 12, 4362–4368 (2018).

    Article  Google Scholar 

  35. Liu, Q., Feng, W., Yang, T., Yi, T. & Li, F. Upconversion luminescence imaging of cells and small animals. Nat. Protoc. 8, 2033–2044 (2013).

    Article  Google Scholar 

  36. Li, Y. et al. Core–shell–shell NaYbF4:Tm@CaF2@NaDyF4 nanocomposites for upconversion/T2-weighted MRI/computed tomography lymphatic imaging. ACS Appl. Mater. Inter. 8, 19208–19216 (2016).

    Article  ADS  Google Scholar 

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Acknowledgements

This project was primarily supported by the National Key R&D Program of China (2017YFA0205100), the National Natural Science Foundation of China (21527801, 21722101, 61729501 and 51720105015), the Strategic Seeding Fund of the UTS Institute for Biomedical Materials and Devices (IBMD) and the Australian Research Council (ARC) Future Fellowship Scheme (to D.J., FT 130100517). The authors thank X. Chen, D. Tu and W. You for their help with lifetime measurements.

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Authors and Affiliations

  1. Department of Chemistry & Institutes of Biomedical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China

    Yuyang Gu, Wei Yuan, Mengya Kong, Yulai Liu, Yilin Gao, Wei Feng & Fuyou Li

  2. Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia

    Zhiyong Guo, Yongtao Liu, Fan Wang, Jiajia Zhou & Dayong Jin

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Contributions

W.F., D.J. and F.L. conceived the project and supervised the research. Y.Gu synthesized the nanoparticles and was primarily responsible for conducting the experiments. Z.G., F.W. and D.J. designed and modified the optical spectroscopy and imaging instruments. Y.Gu, D.J., J.Z., W.F. and F.L. analysed the results, prepared the figures and wrote the manuscript. All authors participated in discussions and editing of the manuscript.

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Correspondence to Wei Feng, Dayong Jin or Fuyou Li.

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This file contains more information about the work, Supplementary Figures 1–37 and Supplementary Tables 1–4.

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Gu, Y., Guo, Z., Yuan, W. et al. High-sensitivity imaging of time-domain near-infrared light transducer. Nat. Photonics 13, 525–531 (2019). https://doi.org/10.1038/s41566-019-0437-z

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