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

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.

References

  1. 1

    De Jong, M., Essers, J. & van Weerden, W. M. Imaging preclinical tumour models: improving translational power. Nat. Rev. Cancer 14, 481–493 (2014).

    CAS  Article  Google Scholar 

  2. 2

    Welsher, K. et al. A route to brightly fluorescent carbon nanotubes for near-infrared imaging in mice. Nat. Nanotech. 4, 773–780 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Yi, H. et al. M13 phage-functionalized single-walled carbon nanotubes as nanoprobes for second near-infrared window fluorescence imaging of targeted tumors. Nano Lett. 12, 1176–11 83 (2012).

    CAS  Article  Google Scholar 

  4. 4

    Hong, G. et al. Through-skull fluorescence imaging of the brain in a new near-infrared window. Nat. Photon. 8, 723–730 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Ghosh, D. et al. Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes. Proc. Natl Acad. Sci. USA 111, 13948–139 53 (2014).

    CAS  Article  Google Scholar 

  6. 6

    Bardhan, N. M., Ghosh, D. & Belcher, A. M. Carbon nanotubes as in vivo bacterial probes. Nat. Commun. 5, 4918 (2014).

    CAS  Article  Google Scholar 

  7. 7

    Welsher, K., Sherlock, S. P. & Dai, H. Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window. Proc. Natl Acad. Sci. USA 108, 8943–8948 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Hong, G. et al. Multifunctional in vivo vascular imaging using near-infrared II fluorescence. Nat. Med. 18, 1841–1846 (2012).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

    Lim, Y. T. et al. Selection of quantum dot wavelengths for biomedical assays and imaging. Mol. Imaging 2, 50–64 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Hong, G. et al. Ultrafast fluorescence imaging in vivo with conjugated polymer fluorophores in the second near-infrared window. Nat. Commun. 5, 4206 (2014).

    CAS  Article  Google Scholar 

  12. 12

    Tsukasaki, Y. et al. Short-wavelength infrared emitting mutimodal probe for non-invasive visualization of phagocyte cell migration in living mice. Chem. Commun. 50, 14356–1435 9 (2014).

    CAS  Article  Google Scholar 

  13. 13

    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, 13002–1300 6 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Dong, B. et al. Facile synthesis of highly photoluminescent Ag2Se quantum dots as a new fluorescent probe in the second near-infrared window for in vivo imaging. Chem. Mater. 25, 2503–2509 (2013).

    CAS  Article  Google Scholar 

  15. 15

    Zhu, C.-N. et al. Ag2Se quantum dots with tunable emission in the second near-infrared window. ACS Appl. Mater. Interfaces 5, 1186–1189 (2013).

    Google Scholar 

  16. 16

    Zhang, Y. Y. et al. Ag2S quantum dot: a bright and biocompatible fluorescent nanoprobe in the second near-infrared window. ACS Nano 6, 3695–3702 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Tsukasaki, Y. et al. Synthesis and optical properties of emission-tunable PbS/CdS core–shell quantum dots for in vivo fluorescence imaging in the second near-infrared window. RSC Adv. 4, 41164–41171 (2014).

    CAS  Article  Google Scholar 

  18. 18

    Chen, O. et al. Compact high-quality CdSe–CdS core–shell nanocrystals with narrow emission linewidths and suppressed blinking. Nat. Mater. 12, 445–451 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Franke, D. et al. Continuous injection synthesis of indium arsenide quantum dots emissive in the short-wavelength infrared. Nat. Commun. 7, 12749 (2016).

    CAS  Article  Google Scholar 

  20. 20

    Zhang, Y. et al. Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice. Biomaterials 34, 3639–3646 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Dubertret, B. et al. In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 298, 1759–1762 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Stroh, M. et al. Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat. Med. 11, 678–682 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Bruns, O. T. et al. Real-time magnetic resonance imaging and quantification of lipoprotein metabolism in vivo using nanocrystals. Nat. Nanotech. 4, 193–201 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Heeren, J. & Bruns, O. Nanocrystals, a new tool to study lipoprotein metabolism and atherosclerosis. Curr. Pharm. Biotechnol. 13, 365–372 (2012).

    CAS  Article  Google Scholar 

  26. 26

    Fay, F. et al. Nanocrystal core lipoprotein biomimetics for imaging of lipoproteins and associated diseases. Curr. Cardiovasc. Imaging Rep. 6, 45–54 (2013).

    Article  Google Scholar 

  27. 27

    Jung, C. et al. Intraperitoneal injection improves the uptake of nanoparticle-labeled high-density lipoprotein to atherosclerotic plaques compared with intravenous injection: a multimodal imaging study in ApoE knockout mice. Circ. Cardiovasc. Imaging 7, 303–311 (2014).

    Article  Google Scholar 

  28. 28

    Jacobs, G. H., Neitz, J. & Deegan, J. F. Retinal receptors in rodents maximally sensitive to ultraviolet light. Nature 353, 655–656 (1991).

    CAS  Article  Google Scholar 

  29. 29

    Foster, H. L., Small, J. D. & Fox, J. G. The Mouse in Biomedical Research: Normative Biology, Immunology, and Husbandry (Academic Press, 2006).

    Google Scholar 

  30. 30

    Berndt, A., Leme, A. S., Paigen, B., Shapiro, S. D. & Svenson, K. L. Unrestrained plethysmograph and anesthetized forced oscillation methods of measuring lung function in 29 inbred strains of mice. Mouse Phenome Databasehttp://phenome.jax.org/db/q?rtn=projects/projdet&reqprojid=351 (2010).

  31. 31

    Hillman, E. M. C. & Moore, A. All-optical anatomical co-registration for molecular imaging of small animals using dynamic contrast. Nat. Photon. 1, 526–530 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Kamoun, W. S. et al. Simultaneous measurement of RBC velocity, flux, hematocrit and shear rate in vascular networks. Nat. Methods 7, 655–660 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Adrian, R. J. Twenty years of particle image velocimetry. Exp. Fluids 39, 159–169 (2005).

    Article  Google Scholar 

  34. 34

    Adrian, R. J. Particle-imaging techniques for experimental fluid mechanics. Annu. Rev. Fluid Mech. 23, 261–304 (1991).

    Article  Google Scholar 

  35. 35

    Shi, Y., Cheng, J. C., Fox, R. O. & Olsen, M. G. Measurements of turbulence in a microscale multi-inlet vortex nanoprecipitation reactor. J. Micromech. Microeng. 23, 75005 (2013).

    Article  Google Scholar 

  36. 36

    Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).

    CAS  Article  Google Scholar 

  37. 37

    Aharoni, A., Mokari, T., Popov, I. & Banin, U. Synthesis of InAs/CdSe/ZnSe core/shell1/shell2 structures with bright and stable near-infrared fluorescence. J. Am. Chem. Soc. 128, 257–264 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Li, J. J. et al. Large-scale synthesis of nearly monodisperse CdSe/CdS core/shell nanocrystals using air-stable reagents via successive ion layer adsorption and reaction. J. Am. Chem. Soc. 125, 12567–12575 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Hines, M. A. & Scholes, G. D. Colloidal PbS nanocrystals with size-tunable near-infrared emission: observation of post-synthesis self-narrowing of the particle size distribution. Adv. Mater. 15, 1844–1849 (2003).

    CAS  Article  Google Scholar 

  40. 40

    Pietryga, J. M. et al. Utilizing the lability of lead selenide to produce heterostructured nanocrystals with bright, stable infrared emission. J. Am. Chem. Soc. 130, 4879–4885 (2008).

    CAS  Article  Google Scholar 

  41. 41

    Supran, G. J. et al. High-performance shortwave-infrared light-emitting devices using core–shell (PbS–CdS) colloidal quantum dots. Adv. Mater. 27, 1437–1442 (2015).

    CAS  Article  Google Scholar 

  42. 42

    Folch, J., Lees, M. & Sloane Stanley, G. H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    CAS  PubMed  Google Scholar 

  43. 43

    Wurdinger, T. et al. A secreted luciferase for ex vivo monitoring of in vivo processes. Nat. Methods 5, 171–173 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Kodack, D. P. et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc. Natl Acad. Sci. USA 109, E3119–E3127 (2012).

    CAS  Article  Google Scholar 

  45. 45

    Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476–4481 (2016).

    CAS  Article  Google Scholar 

  46. 46

    Neher, R. A. et al. Blind source separation techniques for the decomposition of multiply labeled fluorescence images. Biophys. J. 96, 3791–3800 (2009).

    CAS  Article  Google Scholar 

  47. 47

    Meinhart, C. D., Wereley, S. T. & Santiago, J. G. A PIV algorithm for estimating time-averaged velocity fields. J. Fluids Eng. 122, 285–289 (2000).

    Article  Google Scholar 

  48. 48

    Marxen, M., Sullivan, P. E., Loewen, M. R., Èhne, B. J. & Jähne, B. Comparison of Gaussian particle center estimators and the achievable measurement density for particle tracking velocimetry. Exp. Fluids 29, 145–153 (2000).

    Article  Google Scholar 

Download references

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.

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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.

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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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Bruns, O., Bischof, T., Harris, D. et al. Next-generation in vivo optical imaging with short-wave infrared quantum dots. Nat Biomed Eng 1, 0056 (2017). https://doi.org/10.1038/s41551-017-0056

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