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Analytical and Bioanalytical Chemistry

, Volume 409, Issue 12, pp 3067–3076 | Cite as

Label-free visualization of nilotinib-functionalized gold nanoparticles within single mammalian cells by C60- SIMS imaging

  • Anna N. Bloom
  • Hua Tian
  • Christian Schoen
  • Nicholas Winograd
Paper in Forefront

Abstract

Obtaining a comprehensive grasp of the behavior and interaction of pharmaceutical compounds within single cells provides some of the fundamental details necessary for more effective drug development. In particular, the changes ensuing in the carrier, drug, and host environment in targeted drug therapy applications must be explored in greater detail, as these are still not well understood. Here, nilotinib-functionalized gold nanoparticles are examined within single mammalian cells with use of imaging cluster secondary ion mass spectrometry in a model study designed to enhance our understanding of what occurs to these particles once that have been internalized. Nilotinib, several types of gold nanoparticles, and the functionalized combination of the two were surveyed and successfully imaged within single cells to determine uptake and performance. Both nilotinib and the gold particle are able to be distinguished and visualized in the functionalized nanoparticle assembly within the cell. These compounds, while both internalized, do not appear to be present in the same pixels of the chemical image, indicating possible cleavage of nilotinib from the particle after cell uptake. The method provided in this work is a direct measurement of uptake and subcellular distribution of an active drug and its carrier within a framework. The results obtained from this study have the potential to be applied to future studies to provide more effective and specific cellular delivery of a relevant pharmaceutical compound.

Keywords

Secondary ion mass spectrometry Targeted drug therapy Nilotinib Gold nanoparticles 

Notes

Acknowledgements

The generous support and donation of compounds and technical support by Novartis Pharmaceuticals (David Six and Thomas Krucker) is gratefully acknowledged. This project was financially supported by the National Institutes of Health (grant no. 5R01 GM113746-22).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hann MM, Simpson GL. Intracellular drug concentration and disposition – the missing link? Methods. 2014;68(2):283–5. doi: 10.1016/j.ymeth.2014.05.009.CrossRefGoogle Scholar
  2. 2.
    Tufts Center for the Study of Drug Development. Outlook 2015. Boston: Tufts Center for the Study of Drug Development; 2015.Google Scholar
  3. 3.
    Morgan P, Van der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov Today. 2012;17(9-10):419–24. doi: 10.1016/j.drudis.2011.12.020.CrossRefGoogle Scholar
  4. 4.
    Kim D, Jon S. Gold nanoparticles in image-guided cancer therapy. Inorg Chim Acta. 2012;393:154–64. doi: 10.1016/j.ica.2012.07.001.CrossRefGoogle Scholar
  5. 5.
    Emerich DF, Thanos CG. Targeted nanoparticle-based drug delivery and diagnosis. J Drug Target. 2007;15(3):163–83. doi: 10.1080/10611860701231810.CrossRefGoogle Scholar
  6. 6.
    Groneberg DA, Giersig M, Welte T, Pison U. Nanoparticle-based diagnosis and therapy. Curr Drug Targets. 2006;7(6):643–8. doi: 10.2174/138945006777435245.CrossRefGoogle Scholar
  7. 7.
    Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin CA. Gold nanoparticles for biology and medicine. Angew Chem Int Ed. 2010;49(19):3280–94. doi: 10.1002/anie.200904359.CrossRefGoogle Scholar
  8. 8.
    Jeong EH, Jung G, Hong CA, Lee H. Gold nanoparticle (AuNP)-based drug delivery and molecular imaging for biomedical applications. Arch Pharm Res. 2014;37(1):53–9. doi: 10.1007/s12272-013-0273-5.CrossRefGoogle Scholar
  9. 9.
    Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release. 2012;161(2):264–73. doi: 10.1016/j.jconrel.2011.08.017.CrossRefGoogle Scholar
  10. 10.
    Male D, Gromnicova R, McQuaid C. Gold nanoparticles for imaging and drug transport to the CNS. Int Rev Neurobiol. 2016;130:155–98. doi: 10.1016/bs.irn.2016.05.003.CrossRefGoogle Scholar
  11. 11.
    Dasgupta A (2012) In: Dasgupta A (eds) Therapeutic drug monitoring: newer drugs and biomarkers. London: Academic; 2012. p. ix-XGoogle Scholar
  12. 12.
    Moein MM, El Beqqali A, Abdel-Rehim M. Bioanalytical method development and validation: critical concepts and strategies. J Chromatogr B. 2016. doi: 10.1016/j.jchromb.2016.09.028.Google Scholar
  13. 13.
    Passarelli MK, Newman CF, Marshall PS, West A, Gilmore IS, Bunch J, et al. Single-cell analysis: visualizing pharmaceutical and metabolite uptake in cells with label-free 3d mass spectrometry imaging. Anal Chem. 2015;87(13):6696–702. doi: 10.1021/acs.analchem.5b00842.CrossRefGoogle Scholar
  14. 14.
    Bloom A, Winograd N. Dye-enhanced imaging of mammalian cells with SIMS. Surf Interface Anal. 2014;46:177–80. doi: 10.1002/sia.5587.CrossRefGoogle Scholar
  15. 15.
    Bloom AN, Tian H, Winograd N. C60-SIMS imaging of nanoparticles within mammalian cells. Biointerphases. 2016;11(2):02A306. doi: 10.1116/1.4939463.CrossRefGoogle Scholar
  16. 16.
    Haase MF, Grigoriev D, Moehwald H, Tiersch B, Shchukin DG. Nanoparticle modification by weak polyelectrolytes for pH-sensitive pickering emulsions. Langmuir. 2011;27(1):74–82. doi: 10.1021/la1027724.CrossRefGoogle Scholar
  17. 17.
    Hagenhoff B, Breitenstein D, Tallarek E, Mollers R, Niehuis E, Sperber M, et al. Detection of micro- and nano-particles in animal cells by ToF-SIMS 3D analysis. Surf Interface Anal. 2013;45(1):315–9. doi: 10.1002/sia.5141.CrossRefGoogle Scholar
  18. 18.
    Tentschert J, Draude F, Jungnickel H, Haase A, Mantion A, Galla S, et al. TOF-SIMS analysis of cell membrane changes in functional impaired human macrophages upon nanosilver treatment. Surf Interface Anal. 2013;45(1):483–5. doi: 10.1002/sia.5155.CrossRefGoogle Scholar
  19. 19.
    Draude F, Galla S, Pelster A, Tentschert J, Jungnickel H, Haase A, et al. ToF-SIMS and laser-SNMS analysis of macrophages after exposure to silver nanoparticles. Surf Interface Anal. 2013;45(1):286–9. doi: 10.1002/sia.4902.CrossRefGoogle Scholar
  20. 20.
    Graham DJ, Wilson JT, Lai JJ, Stayton PS, Castner DG. Three-dimensional localization of polymer nanoparticles in cells using ToF-SIMS. Biointerphases. 2016;11(2):02A304. doi: 10.1116/1.4934795.CrossRefGoogle Scholar
  21. 21.
    Blay JY, von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin Oncol. 2011;38(2):S3–9. doi: 10.1053/j.seminoncol.2011.01.016.CrossRefGoogle Scholar
  22. 22.
    Wyse RK, Brundin P, Sherer TB. Nilotinib – differentiating the hope from the hype. J Parkinson Dis. 2016;6(3):519–22. doi: 10.3233/Jpd-160904.CrossRefGoogle Scholar
  23. 23.
    Pagan F, Hebron M, Valadez EH, Torres-Yaghi Y, Huang X, Mills RR, et al. Nilotinib effects in Parkinson's disease and dementia with Lewy bodies. J Parkinson Dis. 2016;6(3):503–17. doi: 10.3233/Jpd-160867.CrossRefGoogle Scholar
  24. 24.
    Reinwald M, Schleyer E, Kiewe P, Blau IW, Burmeister T, Pursche S, et al. Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation. Biomed Res Int. 2014;2014:637059. doi: 10.1155/2014/637059.CrossRefGoogle Scholar
  25. 25.
    Jesson G, Brisander M, Andersson P, Demirbuker M, Derand H, Lennernas H, et al. Carbon dioxide-mediated generation of hybrid nanoparticles for improved bioavailability of protein kinase inhibitors. Pharm Res. 2014;31(3):694–705. doi: 10.1007/s11095-013-1191-4.CrossRefGoogle Scholar
  26. 26.
    Cortese B, D'Amone S, Gigli G, Palama IE. Sustained anti-BCR-ABL activity with pH responsive imatinib mesylate loaded PCL nanoparticles in CML cells. Med Chem Commun. 2015;6(1):212–21. doi: 10.1039/c4md00348a.CrossRefGoogle Scholar
  27. 27.
    Lam ATN, Yoon J, Ganbold EO, Singh DK, Kim D, Cho KH, et al. Adsorption and desorption of tyrosine kinase inhibitor erlotinib on gold nanoparticles. J Colloid Interface Sci. 2014;425:96–101. doi: 10.1016/j.jcis.2014.03.032.CrossRefGoogle Scholar
  28. 28.
    Labala S, Mandapalli PK, Kurumaddali A, Venuganti VVK. Layer-by-layer polymer coated gold nanoparticles for topical delivery of imatinib mesylate to treat melanoma. Mol Pharm. 2015;12(3):878–88. doi: 10.1021/mp5007163.CrossRefGoogle Scholar
  29. 29.
    Petrushev B, Boca S, Simon T, Berce C, Frinc I, Dima D, et al. Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy. Int J Nanomed. 2016;11:641–60. doi: 10.2147/IJN.S94064.Google Scholar
  30. 30.
    Berman ESF, Fortson SL, Checchi KD, Wu L, Felton JS, Wu KJJ, et al. Preparation of single cells for imaging/profiling mass spectrometry. J Am Soc Mass Spectrom. 2008;19(8):1230–6. doi: 10.1016/j.jasms.2008.05.006.CrossRefGoogle Scholar
  31. 31.
    Rabbani S, Fletcher JS, Lockyer NP, Vickerman JC. Exploring subcellular imaging on the buncher-ToF J105 3D chemical imager. Surf Interface Anal. 2011;43(1-2):380–4. doi: 10.1002/sia.3457.CrossRefGoogle Scholar
  32. 32.
    Duckett DR, Cameron MD. Metabolism considerations for kinase inhibitors in cancer treatment. Expert Opin Drug Metab Toxicol. 2010;6(10):1175–93. doi: 10.1517/17425255.2010.506873.CrossRefGoogle Scholar
  33. 33.
    Fletcher JS, Rabbani S, Henderson A, Lockyer NP, Vickerman JC. Three-dimensional mass spectral imaging of HeLa-M cells - sample preparation, data interpretation and visualisation. Rapid Commun Mass Spectrom. 2011;25(7):925–32. doi: 10.1002/rcm.4944.CrossRefGoogle Scholar
  34. 34.
    Fu D, Zhou J, Zhu WS, Manley PW, Wang YK, Hood T, et al. Imaging the intracellular distribution of tyrosine kinase inhibitors in living cells with quantitative hyperspectral stimulated Raman scattering. Nat Chem. 2014;6(7):615–23. doi: 10.1038/Nchem.1961.CrossRefGoogle Scholar
  35. 35.
    Robinson MA, Graham DJ, Castner DG. ToF-SIMS depth profiling of cells: z-correction, 3D imaging, and sputter rate of individual NIH/3T3 fibroblasts. Anal Chem. 2012;84(11):4880–5. doi: 10.1021/ac300480g.CrossRefGoogle Scholar
  36. 36.
    Abumiya M, Takahashi N, Niioka T, Kameoka Y, Fujishima N, Tagawa H, et al. Influence of UGT1A1*6,*27, and*28 Polymorphisms on nilotinib-induced hyperbilirubinemia in Japanese patients with chronic myeloid leukemia. Drug Metab Pharmacokinet. 2014;29(6):449–54. doi: 10.2133/dmpk.DMPK-14-RG-031.CrossRefGoogle Scholar
  37. 37.
    Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorg Med Chem. 2009;17(8):2950–62. doi: 10.1016/j.bmc.2009.02.043.CrossRefGoogle Scholar
  38. 38.
    Kolhar P, Anselmo AC, Gupta V, Pant K, Prabhakarpandian B, Ruoslahti E, et al. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proc Natl Acad Sci U S A. 2013;110(26):10753–8. doi: 10.1073/pnas.1308345110.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Anna N. Bloom
    • 1
  • Hua Tian
    • 1
  • Christian Schoen
    • 2
  • Nicholas Winograd
    • 1
  1. 1.Department of ChemistryThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.Nanopartz Inc.LovelandUSA

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