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Mechanism of hard-nanomaterial clearance by the liver

Abstract

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

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Figure 1: Distribution of quantum dots in the liver following systemic intravascular injection.
Figure 2: Nanomaterial sequestration in the liver versus in the systemic circulation: mathematical modelling and in vivo results.
Figure 3: Characterization of in vivo quantum dot uptake in the liver.
Figure 4: In vivo and in vitro results for quantum dot uptake in the liver versus in the spleen.
Figure 5: Nanomaterial uptake by Kupffer cells can be reduced by manipulating flow rate and cellular phenotype.
Figure 6: Mechanism of nanomaterial transport in the liver.

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Acknowledgements

We would to acknowledge the Canadian Institute of Health Research, Natural Sciences and Engineering Research Council, and Collaborative Health Research Program for funding the project. K.M.T. thanks the NSERC Vanier Canada Graduate Scholarship Program and the Surgeon-Scientist Program at the University of Toronto for financial support. S.A.M. thanks the CASL/CIHR Hepatology Fellowship Program and the National CIHR Research Training Program in Hepatitis C for financial support. We would also like to acknowledge M. Peralta and C. Hoculada from the University Health Network Pathology Research Program (Toronto, Canada), D. Holmyard from the Mount Sinai Advanced Bioimaging Centre (Toronto, Canada), F. Xu from the University Health Network Advanced Optical Microscopy Facility (Toronto, Canada), D. White from the Department of Immunology, University of Toronto (Toronto, Ontario), J. Manual, J. Feld and V. Cherepanov from the Toronto Centre for Liver Disease (Toronto, Canada), J. Krieger from the SPARC Biocentre at the Hospital for Sick Children (Toronto, Canada) and A. Black from the Department of Anatomy, National University of Ireland, Galway (Galway, Ireland) for their assistance.

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K.M.T., S.A.M., J.B.C., I.D.M. and W.C.W.C. conceived the idea. K.M.T., S.A.M., O.A.A., I.D.M. and W.C.W.C. analysed the data. K.M.T. and S.A.M. conducted the experiments with assistance from X.-Z.M., V.N.S., J.E., B.O., S.M.F., E.A.S., N.G. and J.M.K. A.Z. performed the mathematical modelling. B.A.A., M.S. and M.A.O. supervised some of the work.

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Correspondence to Ian D. McGilvray or Warren C. W. Chan.

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Tsoi, K., MacParland, S., Ma, XZ. et al. Mechanism of hard-nanomaterial clearance by the liver. Nature Mater 15, 1212–1221 (2016). https://doi.org/10.1038/nmat4718

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