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Glutathione-mediated biotransformation in the liver modulates nanoparticle transport

Abstract

Glutathione-mediated biotransformation in the liver is a well-known detoxification process to eliminate small xenobiotics, but its impacts on nanoparticle retention, targeting and clearance are much less understood than liver macrophage uptake, even though both processes are involved in liver detoxification. By designing a thiol-activatable fluorescent gold nanoprobe that can bind to serum protein and be transported to the liver, we non-invasively imaged the biotransformation kinetics in vivo at high specificity and examined this process at the chemical level. Our results show that glutathione efflux from hepatocytes results in high local concentrations of both glutathione and cysteine in liver sinusoids, which transforms the nanoparticle surface chemistry, reduces its affinity to serum protein and significantly alters its blood retention, targeting and clearance. With this biotransformation, liver detoxification, a long-standing barrier in nanomedicine translation, can be turned into a bridge toward maximizing targeting and minimizing nanotoxicity.

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Fig. 1: Interactions of ICG4-GS-Au25 with sinusoidal GSH efflux in the liver.
Fig. 2: Characterization of ICG-GS-Au25 nanoprobes.
Fig. 3: Effect of sinusoidal GSH efflux on the in vivo behaviour of ICG4-GS-Au25.
Fig. 4: Analysis of the Au25 surface chemistry after in vivo biotransformation.
Fig. 5: Tumour targeting of ICG4-GS-Au25.
Fig. 6: Liver GSH-mediated biotransformation impacting in vivo transport of ICG4-GS-Au25.

Data availability

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

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Acknowledgements

The authors acknowledge financial support from the National Institutes of Health (NIH; R01DK103363 and R01DK115986), the Cancer Prevention Research Institute of Texas (CPRIT; RP160866), the Welch Research Foundation (AT-1974-20180324) and the Cecil H. and Ida Green Professorship in System Biology (to J.Z.) from the University of Texas at Dallas. The authors also thank E. Hernandez and J.T. Hsieh from The University of Texas Southwestern Medical Center for tissue slide preparation.

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J.Z. conceived the idea. J.Z. and X.J. designed the experiments. X.J. conducted the experiments with the assistance of B.D. X.J. discussed and analysed the results with J.Z. J.Z. and X.J. composed the manuscript. All authors commented on the manuscript.

Corresponding author

Correspondence to Jie Zheng.

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Supplementary Information

Supplementary materials, Supplementary Figs. 1–28, Supplementary references.

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Supplementary Movie

Non-invasive in vivo fluorescence imaging of ICG4-GS-Au25 in PBS-treated and DEM-treated mice.

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Jiang, X., Du, B. & Zheng, J. Glutathione-mediated biotransformation in the liver modulates nanoparticle transport. Nat. Nanotechnol. 14, 874–882 (2019). https://doi.org/10.1038/s41565-019-0499-6

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