Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime

Nature Nanotechnology volume 12, pages 1096–1102 (2017)Cite this article

Subjects

Abstract

The glomerular filtration barrier is known as a ‘size cutoff’ slit, which retains nanoparticles or proteins larger than 6–8 nm in the body and rapidly excretes smaller ones through the kidneys. However, in the sub-nanometre size regime, we have found that this barrier behaves as an atomically precise ‘bandpass’ filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10-11). Compared to Au25 (∼1.0 nm), just few-atom decreases in size result in four- to ninefold reductions in renal clearance efficiency in the early elimination stage, because the smaller AuNCs are more readily trapped by the glomerular glycocalyx than larger ones. This unique in vivo nano–bio interaction in the sub-nanometre regime also slows down the extravasation of sub-nanometre AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through an enhanced permeability and retention effect. This discovery highlights the size precision in the body's response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases associated with glycocalyx dysfunction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Renal clearance of different sized AuNCs and schematic diagram of the glomerular filtration membrane.
Figure 2: EM images of the ultrastructure of the glomerular filtration membrane from mice after i.v. injection of PBS, Au25 or Au18.
Figure 3: In vivo behaviour of few-atom AuNCs.
Figure 4: Tumour targeting efficiency and long-term accumulation in the body.

Similar content being viewed by others

References

  1. Ohta, S., Glancy, D. & Chan, W. C. DNA-controlled dynamic colloidal nanoparticle systems for mediating cellular interaction. Science 351, 841–845 (2016).

    Article  CAS  Google Scholar 

  2. Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  Google Scholar 

  3. Albanese, A., Tang, P. S. & Chan, W. C. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012).

    Article  CAS  Google Scholar 

  4. Chithrani, B. D., Ghazani, A. A. & Chan, W. C. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 6, 662–668 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Huang, K. et al. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano 6, 4483–4493 (2012).

    Article  CAS  Google Scholar 

  7. Wang, B., He, X., Zhang, Z., Zhao, Y. & Feng, W. Metabolism of nanomaterials in vivo: blood circulation and organ clearance. Acc. Chem. Res. 46, 761–769 (2013).

    Article  CAS  Google Scholar 

  8. Yu, M. & Zheng, J. Clearance pathways and tumor targeting of imaging nanoparticles. ACS Nano 9, 6655–6674 (2015).

    Article  CAS  Google Scholar 

  9. Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  Google Scholar 

  10. Longmire, M., Choyke, P. L. & Kobayashi, H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine (Lond.) 3, 703–717 (2008).

    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. Haraldsson, B., Nyström, J. & Deen, W. M. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol. Rev. 88, 451–487 (2008).

    Article  CAS  Google Scholar 

  13. Hall, J. E. Guyton and Hall Textbook of Medical Physiology (Elsevier Health Sciences, 2015).

    Google Scholar 

  14. Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    Article  CAS  Google Scholar 

  15. Burns, A. A. et al. Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett. 9, 442–448 (2009).

    Article  CAS  Google Scholar 

  16. Zhou, C. et al. Near-infrared emitting radioactive gold nanoparticles with molecular pharmacokinetics. Angew. Chem. Int. Ed. 124, 10265–10269 (2012).

    Article  Google Scholar 

  17. Zhou, C., Long, M., Qin, Y., Sun, X. & Zheng, J. Luminescent gold nanoparticles with efficient renal clearance. Angew. Chem. Int. Ed. 123, 3226–3230 (2011).

    Article  Google Scholar 

  18. Venturoli, D. & Rippe, B. Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am. J. Physiol. Renal Physiol. 288, F605–F613 (2004).

    Article  Google Scholar 

  19. Rennke, H. G., Cotran, R. S. & Venkatachalam, M. A. Role of molecular charge in glomerular permeability. Tracer studies with cationized ferritins. J. Cell Biol. 67, 638–646 (1975).

    Article  CAS  Google Scholar 

  20. Azubel, M. et al. Electron microscopy of gold nanoparticles at atomic resolution. Science 345, 909–912 (2014).

    Article  CAS  Google Scholar 

  21. Li, G., Jiang, D.-e., Kumar, S., Chen, Y. & Jin, R. Size dependence of atomically precise gold nanoclusters in chemoselective hydrogenation and active site structure. ACS Catal. 4, 2463–2469 (2014).

    Article  CAS  Google Scholar 

  22. Jadzinsky, P. D., Calero, G., Ackerson, C. J., Bushnell, D. A. & Kornberg, R. D. Structure of a thiol monolayer-protected gold nanoparticle at 1.1 Å resolution. Science 318, 430–433 (2007).

    Article  CAS  Google Scholar 

  23. Zheng, J., Petty, J. T. & Dickson, R. M. High quantum yield blue emission from water-soluble Au8 nanodots. J. Am. Chem. Soc. 125, 7780–7781 (2003).

    Article  CAS  Google Scholar 

  24. Jin, R., Zeng, C., Zhou, M. & Chen, Y. Atomically precise colloidal metal nanoclusters and nanoparticles: fundamentals and opportunities. Chem. Rev. 116, 10346–10413 (2016).

    Article  CAS  Google Scholar 

  25. Tang, S. et al. Tailoring renal clearance and tumor targeting of ultrasmall metal nanoparticles with particle density. Angew. Chem. Int. Ed. 128, 16273–16277 (2016).

    Article  Google Scholar 

  26. Liu, J. et al. Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance. J. Am. Chem. Soc. 135, 4978–4981 (2013).

    Article  CAS  Google Scholar 

  27. Singh, A. & Satchell, S. C. Microalbuminuria: causes and implications. Pediatr. Nephrol. 26, 1957–1965 (2011).

    Article  Google Scholar 

  28. Chou, L. Y., Fischer, H. C., Perrault, S. D. & Chan, W. C. Visualizing quantum dots in biological samples using silver staining. Anal. Chem. 81, 4560–4565 (2009).

    Article  CAS  Google Scholar 

  29. Vernier, R. L., Steffes, M. W., Sisson-Ross, S. & Mauer, S. M. Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Kidney Int. 41, 1070–1080 (1992).

    Article  CAS  Google Scholar 

  30. Rubinson, K. A. & Rubinson, J. F. Contemporary Instrumental Analysis (Prentice Hall, 2000).

  31. Uhl, B. et al. The endothelial glycocalyx controls interactions of quantum dots with the endothelium and their translocation across the blood–tissue border. ACS Nano 11, 1498–1508 (2017).

    Article  CAS  Google Scholar 

  32. Nieuwdorp, M. et al. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr. Opin. Lipidol. 16, 507–511 (2005).

    Article  CAS  Google Scholar 

  33. Greenblatt, D. J. Elimination half-life of drugs: value and limitations. Annu. Rev. Med. 36, 421–427 (1985).

    Article  CAS  Google Scholar 

  34. Fang, J., Nakamura, H. & Maeda, H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Del. Rev. 63, 136–151 (2011).

    Article  CAS  Google Scholar 

  35. Liu, J. et al. PEGylation and zwitterionization: pros and cons in the renal clearance and tumor targeting of near-IR-emitting gold nanoparticles. Angew. Chem. Int Ed. 125, 12804–12808 (2013).

    Article  Google Scholar 

  36. Kang, H. et al. Renal clearable organic nanocarriers for bioimaging and drug delivery. Adv. Mater. 28, 8162–8168 (2016).

    Article  CAS  Google Scholar 

  37. Yu, Y. et al. Scalable and precise synthesis of thiolated Au10–12, Au15, Au18, and Au25 nanoclusters via pH controlled CO reduction. Chem. Mater. 25, 946–952 (2013).

    Article  CAS  Google Scholar 

  38. Yao, Q. et al. Two-phase synthesis of small thiolate-protected Au15 and Au18 nanoclusters. Small 9, 2696–2701 (2013).

    Article  CAS  Google Scholar 

  39. Shichibu, Y., Negishi, Y., Tsukuda, T. & Teranishi, T. Large-scale synthesis of thiolated Au25 clusters via ligand exchange reactions of phosphine-stabilized Au11 clusters. J. Am. Chem. Soc. 127, 13464–13465 (2005).

    Article  CAS  Google Scholar 

  40. Das, A. et al. Total structure and optical properties of a phosphine/thiolate-protected Au24 nanocluster. J. Am. Chem. Soc. 134, 20286–20289 (2012).

    Article  CAS  Google Scholar 

  41. Negishi, Y., Nobusada, K. & Tsukuda, T. Glutathione-protected gold clusters revisited: bridging the gap between gold(I)–thiolate complexes and thiolate-protected gold nanocrystals. J. Am. Chem. Soc. 127, 5261–5270 (2005).

    Article  CAS  Google Scholar 

  42. Yu, Y. et al. Identification of a highly luminescent Au22(SG)18 nanocluster. J. Am. Chem. Soc. 136, 1246–1249 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was in part supported by the NIH (1R01DK103363), CPRIT (RP140544) and a start-up fund from the University of Texas at Dallas (to J.Z.).

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The University of Texas at Dallas, 800 West Campbell Road, Richardson, 75080, Texas, USA

    Bujie Du, Xingya Jiang, Qinhan Zhou, Mengxiao Yu & Jie Zheng

  2. Deparment of Chemistry, Carnegie Mellon University, Pittsburgh, 15213, Pennsylvania, USA

    Anindita Das & Rongchao Jin

Authors
  1. Bujie Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xingya Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anindita Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qinhan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengxiao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rongchao Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jie Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.Z. conceived the idea and designed experiments with B.D. and R.J. B.D. performed in vivo experiments and analysed data with J.Z. X.J., Q.Z. and A.D. synthesized AuNCs. X.J. and M.Y. assisted with the in vivo experiment. J.Z. and B.D. wrote the manuscript. J.Z. supervised the project. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Jie Zheng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 14889 kb)

Supplementary information

Supplementary Movie 1 (MP4 578 kb)

Supplementary information

Supplementary Movie 2 (MP4 2250 kb)

Supplementary information

Supplementary Movie 3 (MP4 3263 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, B., Jiang, X., Das, A. et al. Glomerular barrier behaves as an atomically precise bandpass filter in a sub-nanometre regime. Nature Nanotech 12, 1096–1102 (2017). https://doi.org/10.1038/nnano.2017.170

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2017.170

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing