Advertisement

A quantitative study of intercellular heterogeneity in gold nanoparticle uptake across multiple cell lines

  • Tyron Turnbull
  • Benjamin Thierry
  • Ivan KempsonEmail author
Research Paper
  • 40 Downloads

Abstract

Quantification of intercellular heterogeneity in nanoparticle association is of paramount interest in research investigating applications of nanoparticles in the biomedical space. In this work, gold nanoparticle association (AuNP) in cell populations was quantified using synchrotron X-ray fluorescence microscopy (XRF) for 3 different cell lines (PC-3, Caco2 and MDA-MB-231) and 2 nanoparticle co-culture times (30 min and 10% of each respective cell lines’ doubling time). Heterogeneity in association between single cells in the same population was dependant on cell line as well as co-culture time. AuNP association heterogeneity increased with co-culture time for 2 out of the 3 cell lines. Regardless of mean association quantity and measured intercellular heterogeneity, all data were best described by log normal distributions. Mean association between cell lines was statistically different at 30 min, yet indistinguishable at 10% doubling time. Heterogeneity between cell lines which demonstrated statistical differences in distribution can exist despite having statistically indistinguishable means.

Keywords

Nanoparticles Uptake Statistics Distribution Cell population Rare cells 

Notes

Acknowledgements

This research was undertaken on the XFM beamline at the Australian Synchrotron, part of ANSTO.

Funding information

This work was supported by the Australian Government through NH&MRC project grant 1045841, Microscopy Australia at the South Australian Regional Facility, University of South Australia and the Australian Research Council’s Discovery Projects funding scheme (project DP190102119).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

216_2019_2154_MOESM1_ESM.pdf (245 kb)
ESM 1 (PDF 245 kb)

References

  1. 1.
    Saunders NA, Simpson F, Thompson EW, Hill MM, Endo-Munoz L, Leggatt G, et al. Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol Med. 2012;4(8):675–84.CrossRefGoogle Scholar
  2. 2.
    Kessler DA, Austin RH, Levine H. Resistance to chemotherapy: patient variability and cellular heterogeneity. Cancer Res. 2014;74(17):4663–70.CrossRefGoogle Scholar
  3. 3.
    Palmari J, Dussert C, Berthois Y, Penel C, Martin PM. Distribution of estrogen receptor heterogeneity in growing MCF-7 cells measured by quantitative microscopy. Cytometry. 1997;27(1):26–35.CrossRefGoogle Scholar
  4. 4.
    Darbre PD, King RJB. Progression to steroid insensitivity can occur irrespective of the presence of functional steroid receptors. Cell. 1987;51(4):521–8.CrossRefGoogle Scholar
  5. 5.
    Rosti G, Castagnetti F, Gugliotta G, Palandri F, Baccarani M. Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase. Crit Rev Oncol/Hematol. 2012;82(2):159–70.CrossRefGoogle Scholar
  6. 6.
    Turnbull T, Douglass M, Paterson D, Bezak E, Thierry B, Kempson I. Relating intercellular variability in nanoparticle uptake with biological consequence: a quantitative X-ray fluorescence study for radiosensitization of cells. Anal Chem. 2015;87(21):10693–7.CrossRefGoogle Scholar
  7. 7.
    Turnbull T, Douglass M, Williamson NH, Howard D, Bhardwaj R, Lawrence M, et al. Cross-correlative single-cell analysis reveals biological mechanisms of nanoparticle radiosensitization. ACS Nano. 2019:13:5077–90.Google Scholar
  8. 8.
    Ware MJ, Godin B, Singh N, Majithia R, Shamsudeen S, Serda RE, et al. Analysis of the influence of cell heterogeneity on nanoparticle dose response. ACS Nano. 2014;8(7):6693–700.CrossRefGoogle Scholar
  9. 9.
    Hansjosten I, Rapp J, Reiner L, Vatter R, Fritsch-Decker S, Peravali R, et al. Microscopy-based high-throughput assays enable multi-parametric analysis to assess adverse effects of nanomaterials in various cell lines. Arch Toxicol. 2018;92(2):633–49.CrossRefGoogle Scholar
  10. 10.
    Mohan R, Wu Q, Manning M, Schmidt-Ullrich R. Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers. Int J Radiat Oncol Biol Phys. 2000;46(3):619–30.CrossRefGoogle Scholar
  11. 11.
    Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev Cancer. 2005;5(7):516–25.CrossRefGoogle Scholar
  12. 12.
    Laborda F, Bolea E, Cepriá G, Gómez MT, Jiménez MS, Pérez-Arantegui J, et al. Detection, characterization and quantification of inorganic engineered nanomaterials: a review of techniques and methodological approaches for the analysis of complex samples. Anal Chim Acta. 2016;904:10–32.CrossRefGoogle Scholar
  13. 13.
    Wang H, Wu Z, Chen B, He M, Hu B. Chip-based array magnetic solid phase microextraction on-line coupled with inductively coupled plasma mass spectrometry for the determination of trace heavy metals in cells. Analyst. 2015;140(16):5619–26.CrossRefGoogle Scholar
  14. 14.
    Alkilany AM, Murphy CJ. Toxicity and cellular uptake of gold nanoparticles: what we have learned so far? J Nanopart Res. 2010;12(7):2313–33.CrossRefGoogle Scholar
  15. 15.
    Drescher D, Giesen C, Traub H, Panne U, Kneipp J, Jakubowski N. Quantitative imaging of gold and silver nanoparticles in single eukaryotic cells by laser ablation ICP-MS. Anal Chem. 2012;84(22):9684–8.CrossRefGoogle Scholar
  16. 16.
    Malucelli E, Fratini M, Notargiacomo A, Gianoncelli A, Merolle L, Sargenti A, et al. Where is it and how much? Mapping and quantifying elements in single cells. Analyst. 2016;141(18):5221–35.CrossRefGoogle Scholar
  17. 17.
    Büchner T, Drescher D, Traub H, Schrade P, Bachmann S, Jakubowski N, et al. Relating surface-enhanced Raman scattering signals of cells to gold nanoparticle aggregation as determined by LA-ICP-MS micromapping. Anal Bioanal Chem. 2014;406(27):7003–14.CrossRefGoogle Scholar
  18. 18.
    Mueller L, Traub H, Jakubowski N, Drescher D, Baranov VI, Kneipp J. Trends in single-cell analysis by use of ICP-MS. Anal Bioanal Chem. 2014;406(27):6963–77.CrossRefGoogle Scholar
  19. 19.
    Chen HH, Chien CC, Petibois C, Wang CL, Chu YS, Lai SF, et al. Quantitative analysis of nanoparticle internalization in mammalian cells by high resolution X-ray microscopy. J Nanobiotechnol. 2011;9:14.Google Scholar
  20. 20.
    Ivask A, Mitchell AJ, Hope CM, Barry SC, Lombi E, Voelcker NH. Single cell level quantification of nanoparticle–cell interactions using mass cytometry. Anal Chem. 2017;89(16):8228–32.CrossRefGoogle Scholar
  21. 21.
    Ryan CG, Siddons DP, Kirkham R, Dunn PA, Kuczewski A, Moorhead G. et al. The new Maia detector system: methods for high definition trace element imaging of natural material. AIP Conference Proceedings, 2010;1221:9–17Google Scholar
  22. 22.
    Jeynes JCG, Jeynes C, Merchant MJ, Kirkby KJ. Measuring and modelling cell-to-cell variation in uptake of gold nanoparticles. Analyst. 2013;138(23):7070–4.CrossRefGoogle Scholar
  23. 23.
    James SA, Feltis BN, De Jonge MD, Sridhar M, Kimpton JA, Altissimo M, et al. Quantification of ZnO nanoparticle uptake, distribution, and dissolution within individual human macrophages. ACS Nano. 2013;7(12):10621–35.CrossRefGoogle Scholar
  24. 24.
    Detappe A, Tsiamas P, Ngwa W, Zygmanski P, Makrigiorgos M, Berbeco R. The effect of flattening filter free delivery on endothelial dose enhancement with gold nanoparticles. Med Phys. 2013;40(3):031706.Google Scholar
  25. 25.
    Bakht MK, Sadeghi M, Pourbaghi-Masouleh M, Tenreiro C. Scope of nanotechnology-based radiation therapy and thermotherapy methods in cancer treatment. Curr Cancer Drug Targets. 2012;12(8):998–1015.CrossRefGoogle Scholar
  26. 26.
    Torrisi L, Restuccia N, Cuzzocrea S, Paterniti I, Ielo I, Pergolizzi S, et al. Laser-produced Au nanoparticles as X-ray contrast agents for diagnostic imaging. Gold Bull. 2017;50(1):51–60.CrossRefGoogle Scholar
  27. 27.
    Ghorbani M, Hamishehkar H. Redox and pH-responsive gold nanoparticles as a new platform for simultaneous triple anti-cancer drugs targeting. Int J Pharm. 2017;520(1–2):126–38.CrossRefGoogle Scholar
  28. 28.
    Butterworth KT, McMahon SJ, Currell FJ, Prise KM. Physical basis and biological mechanisms of gold nanoparticle radiosensitization. Nanoscale. 2012;4(16):4830–8.CrossRefGoogle Scholar
  29. 29.
    Jain S, Coulter JA, Butterworth KT, Hounsell AR, McMahon SJ, Hyland WB, et al. Gold nanoparticle cellular uptake, toxicity and radiosensitisation in hypoxic conditions. Radiother Oncol. 2014;110(2):342–7.Google Scholar
  30. 30.
    Enüstün BV, Turkevich J. Coagulation of colloidal gold. J Am Chem Soc. 1963;85(21):3317–28.CrossRefGoogle Scholar
  31. 31.
    Liu T, Kempson I, De Jonge M, Howard DL, Thierry B. Quantitative synchrotron X-ray fluorescence study of the penetration of transferrin-conjugated gold nanoparticles inside model tumour tissues. Nanoscale. 2014;6(16):9774–82.CrossRefGoogle Scholar
  32. 32.
    Paterson D, de Jonge MD, McKinlay J, Starritt A, Kusel M, Ryan CG, Kirkham R, Moorhead G, Siddons DP. The X-ray Fluorescence Microscopy Beamline at the Australian Synchrotron. AIP Conference 2011;1365:219–22.Google Scholar
  33. 33.
    Ryan CG. Quantitative trace element imaging using PIXE and the nuclear microprobe. Int J Imaging Syst Technol. 2000;11(4):219–30.CrossRefGoogle Scholar
  34. 34.
    Behrens I, Vila Pena AI, Alonso MJ, Kissel T. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharm Res. 2002;19(8):1185–93.CrossRefGoogle Scholar
  35. 35.
    Niepel M, Spencer SL, Sorger PK. Non-genetic cell-to-cell variability and the consequences for pharmacology. Curr Opin Chem Biol. 2009;13(5–6):556–61.CrossRefGoogle Scholar
  36. 36.
    Wang H, Wang B, Wang M, Zheng L, Chen H, Chai Z, et al. Time-resolved ICP-MS analysis of mineral element contents and distribution patterns in single cells. Analyst. 2015;140(2):523–31.CrossRefGoogle Scholar
  37. 37.
    Chithrani BD, Ghazani AA, Chan WCW. Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells. Nano Lett. 2006;6(4):662–8.CrossRefGoogle Scholar
  38. 38.
    Johnston ST, Faria M, Crampin EJ. An analytical approach for quantifying the influence of nanoparticle polydispersity on cellular delivered dose. J R Soc Interface. 2018;15(144):20180364.Google Scholar
  39. 39.
    Cho EC, 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 (Weinheim an der Bergstrasse, Germany). 2010;6(4):517–22.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tyron Turnbull
    • 1
  • Benjamin Thierry
    • 1
  • Ivan Kempson
    • 1
    Email author
  1. 1.Future Industries InstituteUniversity of South AustraliaMawson LakesAustralia

Personalised recommendations