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Mechanism of hard-nanomaterial clearance by the liver

Nature Materials volume 15, pages 1212–1221 (2016)Cite this article

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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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References

  1. Kim, B. Y., Rutka, J. T. & Chan, W. C. Nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).

    Article  CAS  Google Scholar 

  2. Veiseh, O., Tang, B. C., Whitehead, K. A., Anderson, D. G. & Langer, R. Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug. Discov. 14, 45–57 (2014).

    Article  Google Scholar 

  3. Mulder, W. J. M., Jaffer, F. A., Fayad, Z. A. & Nahrendorf, M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci. Transl. Med. 6, 239sr1 (2014).

    Article  Google Scholar 

  4. Nasongkla, N. et al. Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. Nano Lett. 6, 2427–2430 (2006).

    Article  CAS  Google Scholar 

  5. Jaiswal, J. K., Mattoussi, H., Mauro, J. M. & Simon, S. M. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat. Biotechnol. 21, 47–51 (2002).

    Article  Google Scholar 

  6. Dhar, S., Daniel, W. L., Giljohann, D. A., Mirkin, C. A. & Lippard, S. J. Polyvalent oligonucleotide gold nanoparticle conjugates as delivery vehicles for platinum(IV) warheads. J. Am. Chem. Soc. 131, 14652–14653 (2009).

    Article  CAS  Google Scholar 

  7. Kam, N. W. S., O’Connell, M., Wisdom, J. A. & Dai, H. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proc. Natl Acad. Sci. USA 102, 11600–11605 (2005).

    Article  CAS  Google Scholar 

  8. Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S. & Audet, J. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  9. Zhang, C. et al. Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. Biomaterials 29, 1233–1241 (2008).

    Article  CAS  Google Scholar 

  10. Fonge, H., Huang, H., Scollard, D., Reilly, R. M. & Allen, C. Influence of formulation variables on the biodistribution of multifunctional block copolymer micelles. J. Control. Release 157, 366–374 (2012).

    Article  CAS  Google Scholar 

  11. Ye, L. et al. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots. Nat. Nanotech. 7, 453–458 (2012).

    Article  CAS  Google Scholar 

  12. Fischer, H. C., Liu, L., Pang, K. S. & Chan, W. C. W. Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the rat. Adv. Funct. Mater. 16, 1299–1305 (2006).

    Article  CAS  Google Scholar 

  13. Semmler-Behnke, M. et al. Biodistribution of 1.4- and 18-nm gold particles in rats. Small 4, 2108–2111 (2008).

    Article  CAS  Google Scholar 

  14. De Jong, W. H. et al. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29, 1912–1919 (2008).

    Article  CAS  Google Scholar 

  15. Liu, Z. et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotech. 2, 47–52 (2006).

    Article  Google Scholar 

  16. Yang, S. T. et al. Biodistribution of pristine single-walled carbon nanotubes in vivo. J. Phys. Chem. C 111, 17761–17764 (2007).

    Article  CAS  Google Scholar 

  17. Hauck, T. S., Anderson, R. E., Fischer, H. C., Newbigging, S. & Chan, W. C. W. In vivo quantum-dot toxicity assessment. Small 6, 138–144 (2010).

    Article  CAS  Google Scholar 

  18. Kuwahira, I., Gonzalez, N. C., Heisler, N. & Piiper, J. Changes in regional blood flow distribution and oxygen supply during hypoxia in conscious rats. J. Appl. Physiol. 74, 211–214 (1993).

    Article  CAS  Google Scholar 

  19. Fournier, L. S. et al. Early modifications of hepatic perfusion measured by functional CT in a rat model of hepatocellular carcinoma using a blood pool contrast agent. Eur. Radiol. 14, 2125–2133 (2004).

    Article  Google Scholar 

  20. Miyazaki, S. et al. Investigation on the optimal position for the quantification of hepatic perfusion by use of dynamic contrast-enhanced computed tomography in rats. Radiol. Phys. Technol. 2, 183–188 (2009).

    Article  Google Scholar 

  21. Menger, M. D., Marzi, I. & Messmer, K. In vivo fluorescence microscopy for quantitative analysis of the hepatic microcirculation in hamsters and rats. Eur. Surg. Res. 23, 158–169 (1991).

    Article  CAS  Google Scholar 

  22. MacPhee, P. J., Schmidt, E. E. & Groom, A. C. Intermittence of blood flow in liver sinusoids, studied by high-resolution in vivo microscopy. Am. J. Physiol. Gastrointest. Liver Physiol. 269, G692–G698 (1995).

    Article  CAS  Google Scholar 

  23. Ingham, D. B. Diffusion of aerosols from a stream flowing through a cylindrical tube. J. Aerosol. Sci. 6, 125–132 (1975).

    Article  Google Scholar 

  24. Davies, C. N. Diffusion and sedimentation of aerosol particles from Poiseuille flow in pipes. J. Aerosol. Sci. 4, 317–328 (1973).

    Article  Google Scholar 

  25. Dobrovolskaia, M. A. & McNeil, S. E. Immunological properties of engineered nanomaterials. Nat. Nanotech. 2, 469–478 (2007).

    Article  CAS  Google Scholar 

  26. Lunov, O. et al. Differential uptake of functionalized polystyrene nanoparticles by human macrophages and a monocytic cell line. ACS Nano 5, 1657–1669 (2011).

    Article  CAS  Google Scholar 

  27. Wang, H., Wu, L. & Reinhard, B. M. Scavenger receptor mediated endocytosis of silver nanoparticles into J774A.1 macrophages is heterogeneous. ACS Nano 6, 7122–7132 (2012).

    Article  CAS  Google Scholar 

  28. Sykes, E. A., Chen, J., Zheng, G. & Chan, W. C. W. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 8, 5696–5706 (2014).

    Article  CAS  Google Scholar 

  29. Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C. & Chan, W. C. W. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 9, 1909–1915 (2009).

    Article  CAS  Google Scholar 

  30. Cho, W.-S. et al. Size-dependent tissue kinetics of PEG-coated gold nanoparticles. Toxicol. Appl. Pharmacol. 245, 116–123 (2010).

    Article  CAS  Google Scholar 

  31. Chithrani, B. D. & Chan, W. C. W. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett. 7, 1542–1550 (2007).

    Article  CAS  Google Scholar 

  32. Gao, H. J., Shi, W. D. & Freund, L. B. Mechanics of receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 102, 9469–9474 (2005).

    Article  CAS  Google Scholar 

  33. Cormode, D. P. et al. A versatile and tunable coating strategy allows control of nanocrystal delivery to cell types in the liver. Bioconjug. Chem. 22, 353–361 (2011).

    Article  CAS  Google Scholar 

  34. Cheng, S.-H. et al. Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy. ACS Nano 6, 4122–4131 (2012).

    Article  CAS  Google Scholar 

  35. Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    Article  CAS  Google Scholar 

  36. Sadauskas, E. et al. Kupffer cells are central in the removal of nanoparticles from the organism. Part. Fibre Toxicol. 4, 10–17 (2007).

    Article  Google Scholar 

  37. Bartneck, M. et al. Peptide-functionalized gold nanorods increase liver injury in hepatitis. ACS Nano 6, 8767–8777 (2012).

    Article  CAS  Google Scholar 

  38. Nakashima, M. et al. Pivotal advance: characterization of mouse liver phagocytic B cells in innate immunity. J. Leukoc. Biol. 91, 537–546 (2012).

    Article  CAS  Google Scholar 

  39. Stock, R. J., Cilento, E. V., Reilly, F. D. & McCuskey, R. S. A compartmental analysis of the splenic circulation in rat. Am. J. Physiol. Heart Circ. Physiol. 245, H17–H21 (1983).

    Article  CAS  Google Scholar 

  40. Chadburn, A. The spleen: anatomy and anatomical function. Semin. Hematol. 37, 13–21 (2000).

    Article  CAS  Google Scholar 

  41. Delp, M. D., Evans, M. V. & Duan, C. Effects of aging on cardiac output, regional blood flow, and body composition in Fischer-344 rats. J. Appl. Physiol. 85, 1813–1822 (1998).

    Article  CAS  Google Scholar 

  42. Walkey, C. D., Olsen, J. B., Guo, H., Emili, A. & Chan, W. C. W. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 134, 2139–2147 (2012).

    Article  CAS  Google Scholar 

  43. Jones, S. W. et al. Nanoparticle clearance is governed by Th1/Th2 immunity and strain background. J. Clin. Invest. 123, 3061–3073 (2013).

    Article  CAS  Google Scholar 

  44. Koo, A., Liang, I. Y. & Cheng, K. K. Hepatic sinusoidal responses to intraportal injections of phenylephrine and isoprenaline in the rat. Clin. Exp. Pharmacol. Physiol. 3, 391–395 (1976).

    Article  CAS  Google Scholar 

  45. Hagemann, T. et al. ‘Re-educating’ tumor-associated macrophages by targeting NF-B. J. Exp. Med. 205, 1261–1268 (2008).

    Article  CAS  Google Scholar 

Download references

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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Author notes

  1. Kim M. Tsoi and Sonya A. MacParland: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Rosebrugh Building, Room 407, 164 College Street, Toronto, Ontario M5S 3G9, Canada

    Kim M. Tsoi, Ben Ouyang, Edward A. Sykes, Anton Zilman & Warren C. W. Chan

  2. Division of Orthopaedic Surgery, University of Toronto, 149 College Street, Toronto, Ontario M5T 1P5, Canada

    Kim M. Tsoi

  3. Department of Immunology, University of Toronto, Medical Sciences Building, Room 6271, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada

    Sonya A. MacParland, Saleh M. Fadel & Mario A. Ostrowski

  4. Multi Organ Transplant Program, Toronto General Research Institute, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada

    Xue-Zhong Ma, Vinzent N. Spetzler, Juan Echeverri, Nicolas Goldaracena, Johann M. Kaths, John B. Conneely, Markus Selzner & Ian D. McGilvray

  5. Department of Orthopaedic Surgery, Duke University, Duke University Medical Center, Room 2888, 200 Trent Drive, Durham, North Carolina 27710, USA

    Benjamin A. Alman

  6. Department of Pathology, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada

    Oyedele A. Adeyi

  7. Department of Physics, University of Toronto, 60 St. George Street, Toronto, Ontario M5S 1A7, Canada

    Anton Zilman

  8. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Room 230, Toronto, Ontario M5S 3E1, Canada

    Warren C. W. Chan

  9. Department of Chemical Engineering, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada

    Warren C. W. Chan

  10. Department of Chemistry, University of Toronto, 80 St George Street, Toronto, Ontario M5S 3H6, Canada

    Warren C. W. Chan

  11. Department of Material Science and Engineering, University of Toronto, 160 College Street, Room 450, Toronto, Ontario M5S 3E1, Canada

    Warren C. W. Chan

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Contributions

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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