Cellular uptake and cytotoxicity of unmodified Pr3+:LaF3 nanoparticles

  • Maksim S. PudovkinEmail author
  • Pavel V. Zelenikhin
  • Victoria V. Shtyreva
  • Vladimir G. Evtugyn
  • Vadim V. Salnikov
  • Alexey S. Nizamutdinov
  • Vadim V. Semashko
Research Paper


Pr3+:LaF3 (CPr = 1%) nanoparticles were characterized by means of transmission electron microscopy (TEM), X-ray diffraction, energy-dispersive spectroscopy, and optical spectroscopy. The obtained 14 nm Pr3+:LaF3 (CPr = 1%) crystalline hexagonal-structured nanoparticles contain Pr, La, and F only. The luminescent spectra emission bands corresponded to the emission bands of Pr3+ions. The Pr3+:LaF3 (CPr = 1%) nanoparticles effectively interact with A 549, LEС, and MDCK cells. By means of TEM, it was revealed that after 2 h of the nanoparticle exposure, A 549, MDCK, and LEС cells internalized the nanoparticles and 20–300 nm agglomerates of the nanoparticles packed into 200–500 nm vesicles were found into the cytoplasm. It seems that the internalization occurs via macropinocytosis. In A 549 cells, some vesicles were disrupted and the nanoparticles escaped the vesicles floating freely in the cytoplasm. Flow cytometry showed that all the cells effectively interact with nanoparticles. This interaction leads to cell granularity change. Specifically, A 549, MDCK, and LEС, and cells treated by nanoparticles have the values of size scattered signal 16 ± 2, 20 ± 3, and 39 ± 3%, respectively, comparing with the untreated cells. The Pr3+:LaF3 (CPr = 1%) nanoparticles were not found into the cellular organelles. The cytotoxicity of the Pr3+:LaF3 (CPr = 1%) nanoparticles is not significant at concentrations of 0.05, 0.1, 0.25, and 0.5 g/L.


Pr3+:LaF3 nanoparticles Fluoride nanoparticles Cytotoxicity Cellular uptake Flow cytometry Macropinocytosis Nanobiomedicine 



The biological experiments and TEM microscopy studies were funded by the subsidy allocated to the Kazan Federal University for the state assignment in the sphere of scientific activities [3.1156.2017/4.6] and [3.5835.2017/6.7]. Microscopy studies were carried out at the Interdisciplinary Center of Analytical Microscopy of the Kazan Federal University. The optical spectroscopy and XRD experiments were funded by the research grant of the Kazan Federal University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11051_2019_4628_MOESM1_ESM.pdf (97 kb)
ESM 1 (PDF 97 kb)


  1. Alakshin EM, Gazizulin RR, Klochkov AV, Korableva SL, Safin TR, Safiullin KR, Tagirov MS (2014) Annealing of PrF3 nanoparticles by microwave irradiation. Opt Spectrosc 116(5):721–723. CrossRefGoogle Scholar
  2. Alakshin EM, Klochkov AV, Kondratyeva EI, Korableva SL, Kiiamov AG, Nuzhina DS, Kodjikian S (2016) Microwave-assisted hydrothermal synthesis and annealing of DyF3 nanoparticles. J Nanomater 2016:7148307. CrossRefGoogle Scholar
  3. Bekah D, Cooper D, Kudinov K, Hill C, Seuntjens J, Bradforth S, Nadeau J (2016) Synthesis and characterization of biologically stable, doped LaF3 nanoparticles co-conjugated to PEG and photosensitizers. J Photochem Photobiol A Chem 329:26–34. CrossRefGoogle Scholar
  4. Dong H, Du S, Zheng X, Lyu G, Sun L, Li L, Zhang P, Zhang C, Yan C (2015) Lanthanide nanoparticles: from design toward bioimaging and therapy. Chem Rev 115:10725–10815. CrossRefGoogle Scholar
  5. Froehlich E, Roblegg E (2014) Mucus as barrier for drug delivery by nanoparticles. J Nanosci Nanotechnol 14(1):126–136. CrossRefGoogle Scholar
  6. Gnach A, Lipinski T, Bednarkiewicz A, Rybka J, Capobianco JA (2015) Upconverting nanoparticles: assessing the toxicity. Chem Soc Rev 44(6):1561–1584. CrossRefGoogle Scholar
  7. Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, Grove JR (1999) MDCK (Madin–Darby canine kidney) cells: a tool for membrane permeability screening. J Pharm Sci 88(1):28–33. CrossRefGoogle Scholar
  8. Jalil RA, Zhang Y (2008) Biocompatibility of silica coated NaYF4 upconversion fluorescent nanocrystals. Biomaterials 29:4122–4128. CrossRefGoogle Scholar
  9. Jaque D, Vetrone F (2012) Luminescence nanothermometry. Nanoscale 4(15):4301–4326. CrossRefGoogle Scholar
  10. Kaczkan M, Boruc Z, Fetlinski B, Turczynski S, Malinowski M (2013) Temperature dependence of 3P0 Pr3+ fluorescence dynamics in Y4Al2O9 crystals. Appl Phys B Lasers Opt 113(2):277–283. CrossRefGoogle Scholar
  11. Kamma I, Kommidi P, Reddy BR (2009) High temperature measurement using luminescence of Pr3+ doped YAG and Ho3+ doped CaF2. Phys Status Solidi C 6(S11):S187–S190. CrossRefGoogle Scholar
  12. Kuhn DA, Vanhecke D, Michen B, Blank F, Gehr P, Petri-Fink A, Rothen-Rutishauser B (2014) Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages. Beilstein J Nanotechnol 5(1):1625–1636. CrossRefGoogle Scholar
  13. Ladol J., Khajuria H, Khajuria S, Sheikh HN (2016). Hydrothermal synthesis, characterization and luminescent properties of lanthanide-doped NaLaF4 nanoparticles. Bulletin of Materials Science. 39(4): 943-952CrossRefGoogle Scholar
  14. Lellouche J, Friedman A, Gedanken A, Banin E (2012) Antibacterial and antibiofilm properties of yttrium fluoride nanoparticles. Int J Nanomedicine 7:5611. CrossRefGoogle Scholar
  15. Lim J, Yeap SP, Che HX, Low SC (2013) Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett 8(1):381. CrossRefGoogle Scholar
  16. Ma L, Chen WX, Zheng YF, Zhao J, Xu Z (2007) Microwave-assisted hydrothermal synthesis and characterizations of PrF3 hollow nanoparticles. Mater Lett 61(13):2765–2768. CrossRefGoogle Scholar
  17. Misfeldt DS, Hamamoto ST, Pitelka DR (1976) Transepithelial transport in cell culture. Proc Natl Acad Sci 73(4):1212–1216. CrossRefGoogle Scholar
  18. Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Thompson M (2009) Understanding biophysicochemical interactions at the nano–bio interface. Nat Mater 8(7):543.,557 CrossRefGoogle Scholar
  19. Oh N, Park JH (2014) Endocytosis and exocytosis of nanoparticles in mammalian cells. Int J Nanomedicine 9(Suppl 1):51Google Scholar
  20. Pudovkin MS, Koryakovtseva DA, Lukinova EV, Korableva SL, Khusnutdinova RS, Kiiamov AG, Nizamutdinov AS, Semashko VV (2019) Characterization of Pr-doped LaF3 nanoparticles synthesized by different variations of coprecipitation method. J Nanomater 2019:7549325. CrossRefGoogle Scholar
  21. Pudovkin MS, Morozov OA, Pavlov VV, Korableva SL, Lukinova EV, Osin YN, Evtugyn VG, Safiullin RA, Semashko VV (2017) Physical background for luminescence thermometry sensors based on Pr3+:LaF3 crystalline particles. J Nanomater 2017:3108586. CrossRefGoogle Scholar
  22. Pudovkin MS, Zelenikhin PV, Krasheninnikova AO, Korableva SL, Nizamutdinov AS, Alakshin EM, Semashko VV, Safiullin RA, Kadirov MK (2016) Photoinduced toxicity of PrF3 and LaF3 nanoparticles. Opt Spectrosc 121(4):538–543. CrossRefGoogle Scholar
  23. Pudovkin MS, Zelenikhin PV, Shtyreva V, Morozov OA, Koryakovtseva DA, Pavlov VV et al (2018) Coprecipitation method of synthesis, characterization, and cytotoxicity of Pr3+: LaF3 (CPr = 3, 7, 12, 20, 30%) nanoparticles. J Nanotechnol 2018:8516498. CrossRefGoogle Scholar
  24. Rai VK, Rai DK, Rai SB (2006) Pr3+ doped lithium tellurite glass as a temperature sensor. Sensors Actuators A Phys 128(1):14–17. CrossRefGoogle Scholar
  25. Rakhmatullin RM, Pudovkin MS, Semashko VV (2019) EPR evidence of surface paramagnetic defects formation due to annealing of LaF3 nanoparticles. Magnetic resonance in solids. Electron J 21:4. CrossRefGoogle Scholar
  26. Reynolds ES (1963) The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. The Journal of cell biology. 17(1): 208.CrossRefGoogle Scholar
  27. Ribeiro AR, Gemini-Piperni S, Travassos R, Lemgruber L, Silva RC, Rossi AL et al (2016) Trojan-like internalization of anatase titanium dioxide nanoparticles by human osteoblast cells. Sci Rep 6:23615. CrossRefGoogle Scholar
  28. Sahu D, Kannan GM, Tailang M, Vijayaraghavan R (2016) In vitro cytotoxicity of nanoparticles: a comparison between particle size and cell type. J Nanosci 2016:9. CrossRefGoogle Scholar
  29. Semashko VV, Pudovkin MS, Cefalas AC, Zelenikhin PV, Gavriil VE, Nizamutdinov AS, Kollia Z, Ferraro A, Sarantopoulou E (2018) Tiny rare-earth fluoride nanoparticles activate tumour cell growth via electrical polar interactions. Nanoscale Res Lett 13(1):370. CrossRefGoogle Scholar
  30. Shcherbakov AB, Zholobak NM, Baranchikov AE, Ryabova AV, Ivanov VK (2015) Cerium fluoride nanoparticles protect cells against oxidative stress. Mater Sci Eng C 50:151–159. CrossRefGoogle Scholar
  31. Stearns RC, Paulauskis JD, Godleski JJ (2001) Endocytosis of ultrafine particles by A549 cells. Am J Respir Cell Mol Biol. 24(2):108–115. CrossRefGoogle Scholar
  32. Verma A, Stellacci F (2010) Effect of surface properties on nanoparticle–cell interactions. Small 6(1):12–21. CrossRefGoogle Scholar
  33. Wang K, Ma J, He M, Gao G, Xu H, Sang J, Cui D (2013) Toxicity assessments of near-infrared upconversion luminescent LaF3:Yb,Er in early development of zebrafish embryos. Theranostics 3(4):258. CrossRefGoogle Scholar
  34. Wysokińska E, Cichos J, Zioło E, Bednarkiewicz A, Strządała L, Karbowiak M, Hreniak D, Kałas W (2016) Cytotoxic interactions of bare and coated NaGdF4: Yb3+: Er3+ nanoparticles with macrophage and fibroblast cells. Toxicol in Vitro 32:16–25. CrossRefGoogle Scholar
  35. Ximendes EC, Rocha U, Kumar KU, Jacinto C, Jaque D (2016) LaF3 core/shell nanoparticles for subcutaneous heating and thermal sensing in the second biological-window. Appl Phys Lett 108(25):253103. CrossRefGoogle Scholar
  36. Xing H, Bu W, Ren Q, Zheng X, Li M, Zhang S, Zhou L (2012) A NaYbF4: Tm3+ nanoprobe for CT and NIR-to-NIR fluorescent bimodal imaging. Biomaterials 33(21):5384–5393. CrossRefGoogle Scholar
  37. Yang JM, Yang H, Lin L (2011) Quantum dot nano thermometers reveal heterogeneous local thermogenesis in living cells. ACS Nano 5(6):5067–5071. CrossRefGoogle Scholar
  38. Zhou J, Yu M, Sun Y, Zhang X, Zhu X, Wu Z, Li F (2011) Fluorine-18-labeled Gd3+/Yb3+/Er3+ co-doped NaYF4 nanophosphors for multimodality PET/MR/UCL imaging. Biomaterials 32(4):1148–1156. CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Institute of PhysicsKazan Federal UniversityKazanRussian Federation
  2. 2.Institute of Fundamental Medicine and BiologyKazan Federal UniversityKazanRussian Federation
  3. 3.Interdisciplinary Center for Analytical MicroscopyKazan Federal UniversityKazanRussian Federation

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