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Non-invasive multimodal functional imaging of the intestine with frozen micellar naphthalocyanines

Abstract

There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and provide good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified 20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1,000). Unlike conventional chromophores, nanonaps exhibit non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole-body imaging.

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Figure 1: Spontaneous formation of non-exchangeable F127–naphthalocyanine frozen micelles.
Figure 2: Temperature-mediated CMC switching to generate surfactant-free nanonaps.
Figure 3: Multispectral nanonaps without peak wavelength shifting at ultrahigh optical densities.
Figure 4: Nanonaps pass safely through the intestine following oral administration.
Figure 5: Non-invasive anatomical and functional PA imaging of the intestine using nanonaps.
Figure 6: Seamless nanonap labelling with 64Cu for whole-body PET imaging of the GI tract.

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Acknowledgements

The authors thank L.L. Balos for assistance with histology, C. Cheng for assistance with dynamic light scattering measurements, and E. Huynh and G. Zheng for assistance with photoacoustic spectroscopy. This work was supported by the National Institutes of Health (W.C., R01CA169365; J.F.L., DP5OD017898; M.S., S10OD010393), the Department of Defense (W.C., W81XWH-11-1-0644), the Korean Ministry of Science, ICT and Future Planning (IT Consilience Creative Program; C.K. and J.F.L., NIPA-2013-H0203-13-1001; C.K., NRF-2011-0030075) and a SUNY Research Foundation Collaboration Fund grant.

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Yu.Z. and J.F.L. conceived the project. Yu.Z, M.J., L.J.R., H.H. and J.G. were responsible for most data collection. Yu.Z., P.A. and J.F.L. planned experiments and interpreted the data related to nanonap formulation. H.H., Yi.Z., S.S., T.E.B. and W.C. planned experiments and interpreted the data related to nanonap radiolabelling. Yu.Z., M.J., L.J.R., J.D.H., M.S., C.K. and J.F.L. planned experiments and interpreted the data related to photoacoustic imaging. Yu.Z., J.G. and J.F.L. planned toxicity studies and interpreted the data. Yu.Z., M.J., H.H., J.D.H., W.C., C.K. and J.F.L. wrote the manuscript.

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Correspondence to Weibo Cai, Chulhong Kim or Jonathan F. Lovell.

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The authors declare no competing financial interests.

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Zhang, Y., Jeon, M., Rich, L. et al. Non-invasive multimodal functional imaging of the intestine with frozen micellar naphthalocyanines. Nature Nanotech 9, 631–638 (2014). https://doi.org/10.1038/nnano.2014.130

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