Abstract

For in vivo imaging, the short-wavelength infrared region (SWIR; 1,000–2,000 nm) provides several advantages over the visible and near-infrared regions: general lack of autofluorescence, low light absorption by blood and tissue, and reduced scattering. However, the lack of versatile and functional SWIR emitters has prevented the general adoption of SWIR imaging by the biomedical research community. Here, we introduce a class of high-quality SWIR-emissive indium-arsenide-based quantum dots that are readily modifiable for various functional imaging applications, and that exhibit narrow and size-tunable emission and a dramatically higher emission quantum yield than previously described SWIR probes. To demonstrate the unprecedented combination of deep penetration, high spatial resolution, multicolour imaging and fast acquisition speed afforded by the SWIR quantum dots, we quantified, in mice, the metabolic turnover rates of lipoproteins in several organs simultaneously and in real time as well as heartbeat and breathing rates in awake and unrestrained animals, and generated detailed three-dimensional quantitative flow maps of the mouse brain vasculature.

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Acknowledgements

This work received support from the US National Institutes of Health (NIH) in part through 5-U54-CA151884 (M.G.B.), P01-CA080124 (R.K.J. and D.Fukumura), R35 CA197743, P50 CA165962 and R01-CA126642 (R.K.J.), R01-CA096915 (D.Fukumura), the NIH funded Laser Biomedical Research Center through 4-P41-EB015871-30 (M.G.B.), and the US National Cancer Institute/Federal Share Proton Beam Program Income (R.K.J.); the US National Foundation for Cancer Research (R.K.J.), and the Warshaw Institute for Pancreatic Cancer Research and Massachusetts General Hospital Executive Committee on Research (D.Fukumura); the US Army Research Office through the Institute for Soldier Nanotechnologies (W911NF-13-D-0001; J.A.C., O.C., H.W., G.W.H. and M.G.B.); the US Department of Defence through DoD W81XWH-10-1-0016 (R.K.J.); and the US National Science Foundation (NSF) through ECCS-1449291 (D.Franke and M.G.B.). This work was supported as part of the Massachusetts Institute of Technology (MIT) Center for Excitonics, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DE-SC0001088 (T.S.B. and M.W.B.W.). O.T.B. is supported by an European Molecular Biology Organization long-term fellowship. A.B. is supported by a Deutsche Forschungsgemeinschaft Research Fellowship (BA 4925/1-1). D.Franke is supported by a fellowship of the Evonik Stiftung and fellowship of the Boehringer Ingelheim Fonds. This research was conducted with government support under and awarded by the US Department of Defence, Air Force Office of Scientific Research, National Defence Science and Engineering Graduate Fellowship 32 CFR 168a (J.A.C.). J.H. is supported by a grant from the Fondation Leducq—Triglyceride Metabolism in Obesity and Cardiovascular Disease. L.R. received a Mildred Scheel Fellowship (Deutsche Krebshilfe). D.K.H., D.M.M., I.C. and O.B.A. were supported by NSF GRFP fellowships. J.K. was supported by fellowships from the Deutsche Forschungsgemeinschaft and the SolidarImmun Foundation. C.J.R. and P.T.C.S. acknowledge support from NIH 4-P41-EB015871-30, DP3-DK101024 01, 1-U01-NS090438-01, 1-R01-EY017656 -0, 6A1, 1-R01-HL121386-01A1, the Biosym IRG of Singapore–MIT Alliance Research and Technology Center, the Koch Institute for Integrative Cancer Research Bridge Initiative, Hamamatsu Inc., and the Samsung GRO program. We thank S. Roberge and P. Huang for technical assistance. We also thank QDVision for providing an InAs–CdZnS QD sample (InAs-016) used in this study. We are grateful to Gökhan Hotamisligil for critical discussion and continuing support.

Author information

Author notes

    • Lars Riedemann
    • , Mark W. B. Wilson
    • , Ou Chen
    • , Gyu Weon Hwang
    •  & Jonas Kloepper

    Present addresses: Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, and Clinical Cooperation Unit Neuro-Oncology, German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany (L.R.); Department of Chemistry, University of Toronto, 80 Saint George Street, Toronto, Ontario M5S 3H6, Canada (M.W.B.W.); Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA (O.C.); Korea Institute of Science and Technology, Seoul 02792, Republic of Korea (G.W.H.); Centre Hospitalier Universitaire Vaudois, Département de Médecine Interne, CHUV-UNIL, Rue du Bugnon 46, 1011 Lausanne, Switzerland (J.K.).

    • Oliver T. Bruns
    •  & Thomas S. Bischof

    These authors contributed equally to this work.

Affiliations

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

    • Oliver T. Bruns
    • , Thomas S. Bischof
    • , Daniel K. Harris
    • , Daniel Franke
    • , Jessica A. Carr
    • , Mark W. B. Wilson
    • , Ou Chen
    • , He Wei
    • , Gyu Weon Hwang
    • , Daniel M. Montana
    • , Igor Coropceanu
    • , Odin B. Achorn
    •  & Moungi G. Bawendi
  2. Department of Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Daniel K. Harris
    • , Gyu Weon Hwang
    •  & Daniel M. Montana
  3. Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

    • Yanxiang Shi
    •  & Klavs F. Jensen
  4. Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Cox-7, Boston, Massachusetts 02114, USA.

    • Lars Riedemann
    • , Jonas Kloepper
    • , Dai Fukumura
    •  & Rakesh K. Jain
  5. Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.

    • Alexander Bartelt
  6. Raytheon Vision Systems, Goleta, California 93117, USA.

    • Frank B. Jaworski
  7. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • Christopher J. Rowlands
    •  & Peter T. C. So
  8. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

    • Joerg Heeren
  9. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • Peter T. C. So

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Contributions

O.T.B., T.S.B., D.K.H., D.Franke, L.R., A.B., F.B.J., J.A.C., M.W.B.W., O.C., H.W., G.W.H., D.M.M., I.C., O.B.A. and J.K. performed the experiments. O.T.B, T.S.B., Y.S. and C.J.R. analysed the data, O.T.B., T.S.B. and M.G.B. wrote the paper and were assisted by D.Franke, A.B. and R.K.J. J.H., P.T.C.S, D.Fukumura, K.F.J. and R.K.J. provided guidance on the study design. J.H. provided lipid samples. All authors reviewed and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Oliver T. Bruns or Thomas S. Bischof or Moungi G. Bawendi.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary figures and video captions.

Videos

  1. 1.

    Supplementary Video 1

    Five InAs core-shell quantum dot samples with distinct emission spectra, dissolved in hexanes. Please refer to the Supplementary Information file for the full description.

  2. 2.

    Supplementary Video 2

    SWIR emission from a mouse with activated brown adipose tissue. Please refer to the Supplementary Information file for the full description.

  3. 3.

    Supplementary Video 3

    Biodistribution of PEGylated SWIR QDs (1,200 nm emission) in a mouse. Please refer to the Supplementary Information file for the full description.

  4. 4.

    Supplementary Video 4

    Same as Supplementary Video 3, after reaching equilibrium. Please refer to the Supplementary Information file for the full description.

  5. 5.

    Supplementary Video 5

    Awake mouse injected with PEGylated QDs emitting at 1,080 nm. Please refer to the Supplementary Information file for the full description.

  6. 6.

    Supplementary Video 6

    Imaging of the brain of a mouse with glioblastoma multiforme through a cranial window, during injection of PEGylated QDs. Please refer to the Supplementary Information file for the full description.

  7. 7.

    Supplementary Video 7

    High-speed intravital SWIR microscopy in the healthy hemisphere of a mouse's brain. Please refer to the Supplementary Information file for the full description.

  8. 8.

    Supplementary Video 8

    High-speed intravital SWIR microscopy of the tumour margin of the mouse shown in Supplementary Video 7. Please refer to the Supplementary Information file for the full description.

  9. 9.

    Supplementary Video 9

    Z-stack images of blood flow in the brain of a mouse. Please refer to the Supplementary Information file for the full description.

  10. 10.

    Supplementary Video 10

    Z-resolved imaging of blood flow in the brain of a mouse. Please refer to the Supplementary Information file for the full description.

  11. 11.

    Supplementary Video 11

    Z-resolved imaging of blood flow in the brain of a mouse. Please refer to the Supplementary Information file for the full description.

  12. 12.

    Supplementary Video 12

    Z-resolved imaging of blood flow in the brain of a mouse. Please refer to the Supplementary Information file for the full description.