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.

  • Letter
  • Published:

Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population

Nature Nanotechnology volume 7, pages 62–68 (2012)Cite this article

Subjects

Abstract

Nanoparticles are considered a primary vehicle for targeted therapies because they can pass biological barriers and enter and distribute within cells by energy-dependent pathways1,2,3. So far, most studies have shown that nanoparticle properties, such as size4,5,6 and surface7,8, can influence how cells internalize nanoparticles. Here, we show that uptake of nanoparticles by cells is also influenced by their cell cycle phase. Although cells in different phases of the cell cycle were found to internalize nanoparticles at similar rates, after 24 h the concentration of nanoparticles in the cells could be ranked according to the different phases: G2/M > S > G0/G1. Nanoparticles that are internalized by cells are not exported from cells but are split between daughter cells when the parent cell divides. Our results suggest that future studies on nanoparticle uptake should consider the cell cycle, because, in a cell population, the dose of internalized nanoparticles in each cell varies as the cell advances through the cell cycle.

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: The cell cycle and its role in nanoparticle uptake.
Figure 2: Internalization of nanoparticles and ranking of the concentration of nanoparticles in the cells.
Figure 3: Nanoparticle export is negligible.
Figure 4: Nanoparticle uptake rates during the different phases of the cell cycle.
Figure 5: Nanoparticle uptake in synchronized cell cultures.

Similar content being viewed by others

References

  1. Kagan, V. E. et al. Fantastic voyage and opportunities of engineered nanomaterials: what are the potential risks of occupational exposures? J. Occup. Environ. Med. 52, 943–946 (2010).

    Article  CAS  Google Scholar 

  2. Oberdörster, G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. J. Intern. Med. 267, 89–105 (2010).

    Article  Google Scholar 

  3. Salvati, A. et al. Experimental and theoretical comparison of intracellular import of polymeric nanoparticles and small molecules: toward models of uptake kinetics. Nanomedicine http://dx.doi.org/10.1016/j.nano.2011.03.005 (2011).

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

    Article  CAS  Google Scholar 

  5. He, C. et al. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31, 3657–3666 (2010).

    Article  CAS  Google Scholar 

  6. Rejman, J., Oberle, V., Zuhorn, I. S. & Hoekstra, D. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem. J. 377, 159–169 (2004).

    Article  CAS  Google Scholar 

  7. Lundqvist, M. et al. Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts. Proc. Natl Acad. Sci. USA 105, 14265–14270 (2008).

    Article  CAS  Google Scholar 

  8. Walczyk, D. et al. What the cell ‘sees’ in bionanoscience. J. Am. Chem. Soc. 132, 5761–5768 (2010).

    Article  CAS  Google Scholar 

  9. Jiang, W., Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nature Nanotech. 3, 145–150 (2008).

    Article  CAS  Google Scholar 

  10. 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 

  11. Gratton, S. E. A. et al. The effect of particle design on cellular internalization pathways. Proc. Natl Acad. Sci. USA 105, 11613–11618 (2008).

    Article  CAS  Google Scholar 

  12. Cho, E. C., Au, L., Zhang, Q. & Xia, Y. The effects of size, shape, and surface functional group of gold nanostructures on their adsorption and internalization by cells. Small 6, 517–522 (2010).

    Article  CAS  Google Scholar 

  13. Cho, E. C., Zhang, Q. & Xia, Y. The effect of sedimentation and diffusion on cellular uptake of gold nanoparticles. Nature Nanotech. 6, 385–391 (2011).

    Article  CAS  Google Scholar 

  14. Lesniak, A. et al. Serum heat inactivation affects protein corona composition and nanoparticle uptake. Biomaterials 31, 9511–9518 (2010).

    Article  CAS  Google Scholar 

  15. Xia, X.-R., Monteiro-Riviere, N. A. & Riviere, J. E. An index for characterization of nanomaterials in biological systems. Nature Nanotech. 5, 671–675 (2010).

    Article  CAS  Google Scholar 

  16. Aggarwal, P. et al. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv. Drug Deliv. Rev. 61, 428–437 (2009).

    Article  CAS  Google Scholar 

  17. Wilhelm, C. et al. Interaction of anionic superparamagnetic nanoparticles with cells: kinetic analyses of membrane adsorption and subsequent internalization. Langmuir 18, 8148–8155 (2002).

    Article  CAS  Google Scholar 

  18. Cho, E. C., Xie, J., Wurm, P. A. & Xia, Y. Understanding the role of surface charges in cellular adsorption versus internalization by selectively removing gold nanoparticles on the cell surface with a I2/KI etchant. Nano Lett. 9, 1080–1084 (2009).

    Article  CAS  Google Scholar 

  19. Lin, H.-C. et al. Quantitative measurement of nano-/microparticle endocytosis by cell mass spectrometry. Angew. Chem. Int. Ed. 49, 3460–3464 (2010).

    Article  CAS  Google Scholar 

  20. Trono, J. D. et al. Size, concentration and incubation time dependence of gold nanoparticle uptake into pancreas cancer cells and its future application to X-ray drug delivery system. J. Radiat. Res. 52, 103–109 (2011).

    Article  Google Scholar 

  21. Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nature Mater. 8, 543–557 (2009).

    Article  CAS  Google Scholar 

  22. Colvin, V. L. The potential environmental impact of engineered nanomaterials. Nature Biotechnol. 21, 1166–1170 (2003).

    Article  CAS  Google Scholar 

  23. Rivera Gil, P. et al. Correlating physico-chemical with toxicological properties of nanoparticles: the present and the future. ACS Nano 4, 5527–5531 (2010).

    Article  CAS  Google Scholar 

  24. Errington, R. J. et al. Single cell nanoparticle tracking to model cell cycle dynamics and compartmental inheritance. Cell Cycle 9, 121–130 (2010).

    Article  CAS  Google Scholar 

  25. Summers, H. D. et al. Statistical analysis of nanoparticle dosing in a dynamic cellular system. Nature Nanotech. 6, 170–174 (2011).

    Article  CAS  Google Scholar 

  26. Hartwell, L. & Weinert, T. Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634 (1989).

    Article  CAS  Google Scholar 

  27. Hartwell, L. H., Culotti, J. & Reid, B. Genetic control of the cell-division cycle in yeast, I. Detection of mutants. Proc. Natl Acad. Sci. USA 66, 352–359 (1970).

    Article  CAS  Google Scholar 

  28. Raucher, D. & Sheetz, M. P. Membrane expansion increases endocytosis rate during mitosis. J. Cell Biol. 144, 497–506 (1999).

    Article  CAS  Google Scholar 

  29. Boucrot, E. & Kirchhausen, T. Endosomal recycling controls plasma membrane area during mitosis. Proc. Natl Acad. Sci. USA 104, 7939–7944 (2007).

    Article  CAS  Google Scholar 

  30. Schweitzer, J. K., Burke, E. E., Goodson, H. V. & D'Souza-Schorey, C. Endocytosis resumes during late mitosis and is required for cytokinesis. J. Biol. Chem. 280, 41628–41635 (2005).

    Article  CAS  Google Scholar 

  31. Snijder, B. et al. Population context determines cell-to-cell variability in endocytosis and virus infection. Nature 461, 520–523 (2009).

    Article  CAS  Google Scholar 

  32. Bexiga, M. G. et al. Cationic nanoparticles induce caspase 3-, 7- and 9-mediated cytotoxicity in a human astrocytoma cell line. Nanotoxicology http://dx.doi.org/10.3109/17435390.2010.539713 (2011).

  33. Shapero, K. et al. Time and space resolved uptake study of silica nanoparticles by human cells. Mol. BioSyst. 7, 371–378 (2011).

    Article  CAS  Google Scholar 

  34. Steel, G. G. Growth Kinetics of Tumors: Cell Population Kinetics in Relation to the Growth and Treatment of Cancer (Oxford Univ. Press, 1977).

  35. 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 Deliv. Rev. 63, 136–151 (2011).

    Article  CAS  Google Scholar 

  36. Ruoslahti, E., Bhatia, S. N. & Sailor, M. J. Targeting of drugs and nanoparticles to tumors. J. Cell Biol. 188, 759–768 (2010).

    Article  CAS  Google Scholar 

  37. Wang, M. & Thanou, M. Targeting nanoparticles to cancer. Pharmacol. Res. 62, 90–99 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding for the project was generously provided by the INSPIRE (Integrated NanoScience Platform for Ireland) programme, funded by the Irish Government's Programme for Research in Third Level Institutions, Cycle 4, National Development Plan 2007-2013 (J.A.K.), and the Irish Research Council for Science, Engineering and Technology (C.Å.), and is based on works supported by the Small Collaborative project NeuroNano funded by the European Commission 7th Framework Programme (NNP4-SL-2008-214547), Science Foundation Ireland (grant nos SFI/SRC/B1155 and 09/RFP/MTR2425) and the European Science Foundation Research Networking Programme EpitopeMap. A. Blanco (Conway Institute Flow Cytometry Facility, University College Dublin) is acknowledged for technical support with flow cytometry. Use of the Conway Institute Imaging Facility (University College Dublin) is also acknowledged. Endothelial hCMEC/D3 cells were provided by F. Miller and B.B. Wecksler (French National Institute of Health and Medical Research, Inserm, Paris, France).

Author information

Authors and Affiliations

  1. Centre for BioNano Interactions, School of Chemistry and Chemical Biology and Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, 4, Belfield, Ireland

    Jong Ah Kim, Christoffer Åberg, Anna Salvati & Kenneth A. Dawson

Authors
  1. Jong Ah Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christoffer Åberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Salvati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenneth A. Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.A.K. performed experiments, analysed and interpreted data, and wrote the paper. C.Å. developed the numerical simulations and analytical tools, analysed and interpreted data, and wrote the paper. A.S. supervised the experimental work, analysed and interpreted data, and wrote the paper. K.A.D. interpreted data and wrote the paper.

Corresponding authors

Correspondence to Anna Salvati or Kenneth A. Dawson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 3851 kb)

Supplementary information

Supplementary information (PPTX 367 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J., Åberg, C., Salvati, A. et al. Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. Nature Nanotech 7, 62–68 (2012). https://doi.org/10.1038/nnano.2011.191

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2011.191

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