Next-generation in vivo optical imaging with short-wave infrared quantum dots

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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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Figure 1: Short-wave infrared quantum dots for next generation in vivo optical imaging.
Figure 2: InAs core–shell quantum dots with high quantum yield and size-tunable emission for functional and high-speed SWIR imaging.
Figure 3: QD nanosomes for metabolic imaging.
Figure 4: High-speed SWIR imaging for contact-free monitoring of heart and respiratory rate in anaesthetized and awake mice using QD phospholipid micelles.
Figure 5: High-speed intravital imaging using QD composite particles.
Figure 6: High-resolution, high-speed intravital imaging using QD composite particles.
Figure 7: High-resolution, high-speed SWIR intravital imaging to generate flow maps of microvascular networks using QD composite particles.

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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

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.

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

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Supplementary information

Supplementary Information

Supplementary figures and video captions. (PDF 6792 kb)

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. (MOV 2521 kb)

Supplementary Video 2

SWIR emission from a mouse with activated brown adipose tissue. Please refer to the Supplementary Information file for the full description. (MOV 1309 kb)

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. (MOV 5674 kb)

Supplementary Video 4

Same as Supplementary Video 3, after reaching equilibrium. Please refer to the Supplementary Information file for the full description. (MOV 4812 kb)

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. (MOV 4035 kb)

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. (MOV 29665 kb)

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. (MOV 8493 kb)

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. (MOV 8305 kb)

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. (AVI 2350 kb)

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. (MOV 10131 kb)

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. (MOV 7114 kb)

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. (AVI 1801 kb)

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