Izvestiya of Saratov University.


ISSN 1817-3020 (Print)
ISSN 2542-193X (Online)

For citation:

Verkhovskii R. A., Anisimov R. A., Lomova M. V., Tuchina D. K., Lazareva E. N., Doronkina A. A., Mylnikov A. M., Navolokin N. A., Kochubey V. I., Yanina I. I. Cytotoxicity of various types of coated upconversion nanoparticles. Overview. Izvestiya of Saratov University. Physics , 2022, vol. 22, iss. 4, pp. 357-373. DOI: 10.18500/1817-3020-2022-22-4-357-373, EDN: DLYOKR

This is an open access article distributed under the terms of Creative Commons Attribution 4.0 International License (CC-BY 4.0).
Published online: 
Full text:
(downloads: 159)
Article type: 

Cytotoxicity of various types of coated upconversion nanoparticles. Overview

Verkhovskii Roman A., Saratov State University
Anisimov Roman A., Saratov State University
Lomova Maria V., Saratov State University
Tuchina Daria K., Saratov State University
Lazareva Ekaterina Nikolaevna, Saratov State University
Doronkina Anna A., Saratov State University
Mylnikov Artyom M., Saratov State Medical University named after V. I. Razumovsky
Navolokin Nikita Aleksandrovich, Saratov State Medical University named after V. I. Razumovsky
Kochubey Vyacheslav Ivanovich, Saratov State University
Yanina Irina Iur'evna, Saratov State University

Background and Objectives: The object of the study was the cytotoxicity of various types of coated upconversion nanoparticles. The aim is to overview the literature on the cytotoxicity of various types of upconversion nanoparticles without/with coating and to search for their maximum permissible concentration when applied to cell. Materials and Methods: The approach used has been the analysis of recent publications on the topic. Results: Upconversion nanoparticles are promising for fluorescence imaging and cancer therapy. Nanoparticles with additional shells or functionalized by surface coating with targeted or photoactive molecules are considered. The toxicological effect of nanoparticles on living organisms is of decisive importance when they are used in therapy or diagnostics. The “dark” cytotoxicity of particles is considered. The cytotoxicity of particles depends on the total number of nanoparticles that have penetrated into the cell. Conclusion: Based on the analysis of a large number of publications, it can be concluded that nanoparticles coated with silicon dioxide (SiO2) are characterized by the least cytotoxic effect, which opens up prospects for the use of this type of nanoparticles in medical practice. 

The study was supported by a grant Russian Science Foundation No. 21-72-10057, https://rscf.ru/project/21-72-10057/.
  1. Wang M., Abbineni G., Clevenger A., Mao C., Xu S. Upconversion nanoparticles: Synthesis, surface modification and biological applications. Nanomed. : Nanotechnol. Biol. Med., 2011, vol. 7, pp. 710–729. https://doi.org/10.1016/j.nano.2011.02.013
  2. Cao Y., Wu J., Zheng X., Lu Y., Piper J. A., Lu Y., Packer N. H. Assessing the activity of antibodies conjugated to upconversion nanoparticles for immunolabeling. Anal. Chim. Acta, 2022, vol. 1209, pp. 339863. https://doi.org/10.1016/j.aca.2022.339863
  3. Li Y., Chen C., Liu F., Liu J. Engineered lanthanidedoped upconversion nanoparticles for biosensing and bioimaging application. Microchim. Acta, 2022, vol. 189, pp. 109. https://doi.org/10.1007/s00604-022-05180-1
  4. Liang G., Wang H., Shi H., Wang H., Zhu M., Jing A., Li J., Li G. Recent progress in the development of upconversion nanomaterials in bioimaging and disease treatment. J. Nanobiotechnol., 2020, vol. 18, pp. 154. https://doi.org/10.1186/s12951-020-00713-3
  5. Rafique R., Kailasa S. K., Park T. J. Recent advances of upconversion nanoparticles in theranostics and bioimaging applications. Trends Anal. Chem., 2019, vol. 120, no. 115646, pp. 1–19 https://doi.org/10.1016/j.trac.2019.115646
  6. Ai X., Lyu L., Zhang Y., Tang Y., Mu J., Liu F., Zhou Y., Zuo Z., Liu G., Xing B. Remote regulation of membrane channel activity by site-specific localization of lanthanide-doped upconversion nanocrystals. Angew. Chem. Int. Ed., 2017, vol. 56, no. 11, pp. 3031–3035. https://doi.org/10.1002/anie.201612142
  7. Sun M., Xu L., Ma W., Wu X., Kuang H., Wang L., Xu C. Phototherapy: Hierarchical plasmonic nanorods and upconversion core-satellite nanoassemblies for multimodal imaging-guided combination phototherapy. Adv. Mater., 2016, vol. 28, no. 5, pp. 897. https://doi.org/10.1002/adma.201670033
  8. Wang C., Tao H., Cheng L., Liu Z. Near-infrared light induced in vivo photodynamic therapy of cancer based on upconversion nanoparticles. Biomaterials, 2011, vol. 32, no. 26, pp. 6145–6154. https://doi.org/10.1016/j.biomaterials.2011.05.007
  9. Tian G., Zhang X., Gu Z., Zhao Y. Recent advances in upconversion nanoparticles-based multifunctional nanocomposites for combined cancer therapy. Adv. Mater., 2015, vol. 27, no. 47, pp. 7692–7712. https://doi.org/10.1002/adma.201503280
  10. Wang M., Hu C., Su Q. Luminescent Lifetime Regulation of Lanthanide-Doped Nanoparticles for Biosensing. Biosensors, 2022, vol. 12, no. 2, pp. 131. https://doi.org/10.3390/bios12020131
  11. He S., Song J., Liu J., Liu L., Qu J., Cheng Z. Enhancing Photoacoustic Intensity of Upconversion Nanoparticles by Photoswitchable Azobenzene-Containing Polymers for Dual NIR-II and Photoacoustic Imaging In Vivo. Adv. Opt. Mater., 2019, vol. 7, pp. 1900045. https://doi.org/10.1002/adom.201900045
  12. Yuan S., Liu Z., Liang T., Jin D., Wang H., Qiao R., Dong M., Gong P. Au-decorated NaYF4:Yb,Tm@NaGdF4:Yb@TiO2 nanophotosensitizers for photodynamic therapy and MR/PET imaging. Mater. Lett., 2022, vol. 314, pp. 131926. https://doi.org/10.1016/j.matlet.2022.131926
  13. Ni J., Xu H., Zhong Y., Zhou Y., Hu S. Activatable UCL/CT/MR-enhanced in vivo imaging-guided radiotherapy and photothermal therapy. J. Mater. Chem. B, 2022, vol. 10, pp. 549–561. https://doi.org/10.1039/D1TB02006D
  14. Ge J., Chen L., Huang B., Gao Y., Zhou D., Zhou Y., Chen C., Wen L., Li Q., Zeng J., Zhong Z., Gao M. Anchoring Group-Mediated Radiolabeling of Inorganic Nanoparticles – A Universal Method for Constructing Nuclear Medicine Imaging Nanoprobes. ACS Appl. Mater. Interfaces., 2022, vol. 14, no. 7, pp. 8838–8846. https://doi.org/10.1021/acsami.1c23907
  15. Lisjak D., Plohl O., Ponikvar-Svet M., Majaron B. Dissolution of upconverting fluoride nanoparticles in aqueous suspensions. RSC Adv., 2015, vol. 5, pp. 27393–27397. https://doi.org/10.1039/C5RA00902B
  16. Plohl O., Kralj S., Majaron B. Fröhlich E., Ponikvar-Svet M., Makovec D., Lisjak D. Amphiphilic coatings for the protection of upconverting nanoparticles against dissolution in aqueous media. Dalton Trans., 2017, vol. 46, pp. 6975–6984. https://doi.org/10.1039/C7DT00529F
  17. Andresen E. Würth C., Prinz C., Michaelis M., Resch-Genger U. Time-resolved luminescence spectroscopy for monitoring the stability and dissolution behaviour of upconverting nanocrystals with different surface coatings. Nanoscale, 2020, vol. 12, pp. 12589–12601. https://doi.org/10.1039/D0NR02931A
  18. Saleh M. I., Rьhl B., Wang S., Radnik J., You Y., ReschGenger U. Assessing the protective effects of different surface coatings on NaYF4:Yb3+, Er3+ upconverting nanoparticles in buffer and DME M. Sci. Rep., 2020, vol. 10, pp. 1–11. https://doi.org/10.1038/S41598-020-76116-Z
  19. Adan A., Kiraz Y., Baran Y. Cell Proliferation and Cytotoxicity Assays. Curr. Pharm. Biotechnol., 2016, vol. 17, no. 14, pp. 1213–1221. https://doi.org/10.2174/1389201017666160808160513
  20. Zhou J., Liu Z., Li F. Upconversion nanophosphors for small-animal imaging. Chem. Soc. Rev., 2012, vol. 41, pp. 1323–1349. https://doi.org/10.1039/C1CS15187H
  21. Chávez-García D., Juárez-Moreno K., Campos C. H., Tejeda E. M., Alderete J. B., Hirata G. A. Cytotoxicity, genotoxicity and uptake detection of folic acid-functionalized green upconversion nanoparticles Y2O3/Er3+, Yb3+ as biolabels for cancer cells. J. Mater. Sci., 2018, vol. 53, no. 9, pp. 6665–6680. https://doi.org/10.1007/s10853-017-1946-0
  22. Chavez D. H., Juarez-Moreno K., Hirata G. A. Aminosilane functionalization and cytotoxicity effects of upconversion nanoparticles Y2O3 and Gd2O3 Co-Doped with Yb3+ and Er3+. Nanobiomedicine, 2016, vol. 3, no. 1, pp. 1–7. https://doi.org/10.5772/62252
  23. Gu Y., Qiao X., Zhang J., Sun Y., Tao Y., Qiao S.-X. Effects of surface modification of upconversion nanoparticles on cellular uptake and cytotoxicity. Chem. Res. Chin. Univ., 2016, vol. 32, no. 3, pp. 474–479. https://doi.org/10.1007/s40242-016-6026-5
  24. Das G. K., Stark D., Kennedy I. M. Potential Toxicity of Up-Converting Nanoparticles Encapsulated with a Bilayer Formed by Ligand Attraction. Langmuir, 2014, vol. 30, no. 27, pp. 8167–8176. https://doi.org/10.1021/la501595f
  25. Atabaev T. Sh., Lee J. H., Han D. W., Hwang Y. H., Kim H. K. Cytotoxicity and cell imaging potentials of submicron color-tunable yttria particles. J. Biomed. Mater. Res. A, 2012, vol. 100, no. 9, pp. 2287–2294. https://doi.org/10.1002/jbm.a.34168
  26. Gao G., Zhang C., Zhou Z., Zhang X., Ma J., Li C., Jin W., Cui D. One-pot hydrothermal synthesis of lanthanide ions doped one-dimensional upconversion submicrocrystals and their potential application in vivo CT imaging. Nanoscale, 2013, vol. 5, no. 1, pp. 351–362. https://doi.org/10.1039/C2NR32850J
  27. Gupta B. K., Narayanan T. N., Vithayathil S. A., Lee Y., Koshy S., Reddy A. L., Saha A., Shanker V., Singh V. N., Kaipparettu B. A. Martí A. A., Ajayan P. M. Highly luminescent-paramagnetic nanophosphor probes for in vitro high-contrast imaging of human breast cancer cells. Small, 2012, vol. 8, no. 19, pp. 3028–3034. https://doi.org/10.1002/smll.201200909
  28. Wang C., He M., Chen B., Hu B. Study on cytotoxicity, cellular uptake and elimination of rare-earth-doped upconversion nanoparticles in human hepatocellular carcinoma cells. Ecotoxicol. Environ. Saf., 2020, vol. 203, no. 110951, pp. 1–10. https://doi.org/10.1016/j.ecoenv.2020.110951
  29. Hemmer E., Yamano T., Kishimoto H., Venkatachalam N., Hyodo H., Soga K. Cytotoxic aspects of gadolinium oxide nanostructures for up-conversion and NIR bioimaging. Acta Biomater., 2013, vol. 9, no. 1, pp. 4734–4743. https://doi.org/10.1016/j.actbio.2012.08.045
  30. Zhang J., Liu F., Li T., He X., Wang Z. Surface charge effect on the cellular interaction and cytotoxicity of NaYF4:Yb3+, Er3+@SiO2 nanoparticles. RSC Adv., 2015, vol. 5, pp. 7773–7780. https://doi.org/10.1039/C4RA11374H
  31. Bae Y. M., Park Y. I., Nam S. H., Kim J. H., Lee K., Kim H. M., Yoo B., Choi J. S., Lee K. T., Hyeon T., Suh Y. D. Endocytosis, intracellular transport, and exocytosis of lanthanide-doped upconverting nanoparticles in single living cells. Biomaterials, 2012, vol. 33, no. 35, pp. 9080–9086. https://doi.org/10.1016/j.biomaterials.2012.08.039
  32. Guller A., Generalova A. N., Petersen E. V., Nechaev A. V., Trusova I. A., Landyshev N. N., Nadort A., Grebenik E. A., Deyev S. M., Shekhter A. B., Zvyagin A. V. Cytotoxicity and non-specific cellular uptake of bare and surface-modified upconversion nanoparticles in human skin cells. Nano Res., 2015, vol. 8, no. 1546, pp. 1–17. https://doi.org/10.1007/s12274-014-0641-6
  33. Li R., Ji Z., Dong J., Chang C. H., Wang X., Sun B., Wang M., Liao Y. P., Zink J. I., Nel A. E., Xia T. Enhancing the imaging and biosafety of upconversion nanoparticles through phosphonate coating. ACS Nano, 2015, vol. 9, no. 3, pp. 3293–3306. https://doi.org/10.1021/acsnano.5b00439
  34. Gnach A., Lipinski T., Bednarkiewicz A., Rybka J., Capobianco J. A. Upconverting nanoparticles: Assessing the toxicity. Chem. Soc. Rev., 2015, vol. 44, pp. 1561–1584. https://doi.org/10.1039/C4CS00177J
  35. Torresan M. F., Wolosiuk A. Critical Aspects on the Chemical Stability of NaYF4-Based Upconverting Nanoparticles for Biomedical Applications. ACS Appl. Bio. Mater., 2021, vol. 4, no. 2, pp. 1191–1210. https://doi.org/10.1021/acsabm.0c01562
  36. Xia A., Chen M., Gao Y., Wu D., Feng W., Li F. Gd3+ complex-modified NaLuF4-based upconversion nanophosphors for trimodality imaging of NIR-to-NIR upconversion luminescence, X-Ray computed tomography and magnetic resonance. Biomaterials, 2012, vol. 33, no. 21, pp. 5394–5405. https://doi.org/10.1016/j.biomaterials.2012.04.025
  37. Abdul Jalil R., Zhang Y. Biocompatibility of silica coated NaYF(4) upconversion fluorescent nanocrystals. Biomaterials, 2008, vol. 29, no. 30, pp. 4122–4128. https://doi.org/10.1016/j.biomaterials.2008.07.012
  38. Guo H., Hao R., Qian H., Sun S., Sun D., Yin H., Liu Z., Liu X. Upconversion nanoparticles modified with aminosilanes as carriers of DNA vaccine for foot-andmouth disease. Appl. Microbiol. Biotechnol., 2012, vol. 95, no. 5, pp. 1253–1263. https://doi.org/10.1007/s00253-012-4042-z
  39. Li C., Yang D., Ma P., Chen Y., Wu Y., Hou Z., Dai Y., Zhao J., Sui C., Lin J. Multifunctional upconversion mesoporous silica nanostructures for dual modal imaging and in vivo drug delivery. Small, 2013, vol. 9, no. 24, pp. 4150–4159. https://doi.org/10.1002/smll.201301093
  40. Ma J., Huang P., He M., Pan L., Zhou Z., Feng L., Gao G., Cui D. Folic acid-conjugated LaF3:Yb,Tm@SiO2 nanoprobes for targeting dualmodality imaging of upconversion luminescence and X-ray computed tomography. J. Phys. Chem. B, 2012, vol. 116, no. 48, pp. 14062–14070. https://doi.org/10.1021/jp309059u
  41. Li X., Tang Y., Xu L., Kong X., Zhang L., Chang Y., Zhao H., Zhang H., Liu X. Dependence between cytotoxicity and dynamic subcellular localization of upconversion nanoparticles with different surface charges. RSC Adv., 2017, vol. 7, no. 53, pp. 33502–33509. https://doi.org/10.1039/C7RA04487A
  42. Zhou N., Qiu P., Wang K., Fu H., Gao G., He R., Cui D. Shape-controllable synthesis of hydrophilic NaLuF4:Yb,Er nanocrystals by a surfactant-assistant two-phase system. Nanoscale Res. Lett., 2013, vol. 8, no. 1, pp. 518. https://doi.org/10.1186/1556-276X-8-518
  43. Liu C., Shao H., Li D., Sui X., Liu N., Rahman S. U., Li X., Arany P. R. Safety and efficacy of citric acidupconverting nanoparticles for multimodal biological imaging in BALB/c mice. Photodiagnosis Photodyn. Ther., 2021, vol. 36, pp. 102485. https://doi.org/10.1016/j.pdpdt.2021.102485
  44. Vedunova M. V., Mishchenko T. A., Mitroshina E. V., Ponomareva N. V., Yudintsev A. V., Generalova A. N. Cytotoxic effects of upconversion nanoparticles in primary hippocampal cultures. RSC Adv., 2016, vol. 6, no. 40, pp. 33656–33665. https://doi.org/10.1039/C6RA01272H
  45. Wang C., Cheng L., Xu H., Liu Z. Towards whole-body imaging at the single cell level using ultra-sensitive stem cell labeling with oligo-arginine modified upconversion nanoparticles. Biomaterials, 2012, vol. 33, no. 19, pp. 4872–4881. https://doi.org/10.1016/j.biomaterials.2012.03.047
  46. Chatterjee D. K., Rufaihah A. J., Zhang Y. Upconversion fluorescence imaging of cells and small animals using lanthanide doped nanocrystals. Biomaterials, 2008, vol. 29, no. 7, pp. 937–943. https://doi.org/10.1016/j.biomaterials.2007.10.051
  47. Zhao L., Kutikov A., Shen J., Duan C., Song J., Han G. Stem cell labeling using polyethylenimine conjugated (α-NaYbF4:Tm3+)/CaF2 upconversion nanoparticles. Theranostics, 2013, vol. 3, no. 4, pp. 249–257. https://doi.org/10.7150/thno.5432
  48. Yang D., Dai Y., Ma P., Kang X., Cheng Z., Li C., Lin J. One-step synthesis of small-sized and water-soluble NaREF4 upconversion nanoparticles for in vitro cell imaging and drug delivery. Chemistry, 2013, vol. 19, no. 8, pp. 2685–2694. https://doi.org/10.1002/chem.201203634
  49. Himmelstoß S. F., Hirsch T. Long-Term Colloidal and Chemical Stability in Aqueous Media of NaYF4-Type Upconversion Nanoparticles Modified by Ligand-Exchange. Part. Part. Syst. Charact., 2019, vol. 36, no. 10, pp. 1900235. https://doi.org/10.1002/ppsc.201900235
  50. Kembuan C., Oliveira H., Graf C. Effect of different silica coatings on the toxicity of upconversion nanoparticles on RAW 264.7 macrophage cells. Beilstein J. Nanotechnol., 2021, vol. 12, pp. 35–48. https://doi.org/10.3762/bjnano.12.3
  51. 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., 2006, vol. 6, pp. 662–668. https://doi.org/10.1021/nl052396o
  52. Chen G., Ohulchanskyy T. Y., Kumar R., Ågren H., Prasad P. N. Ultrasmall monodisperse NaYF4:Yb3+/Tm3+ nanocrystals with enhanced nearinfrared to near-infrared upconversion photoluminescence. ACS Nano, 2010, vol. 4, pp. 3163–3168. https://doi.org/10.1021/nn100457j
  53. Bastos V., Oskoei P., Andresen E., Saleh M. I. Rühle B., Resch-Genger U., Oliveira H. S. Stability, dissolution, and cytotoxicity of NaYF4-upconversion nanoparticles with different coatings. Sci. Rep., 2022, vol. 12, no. 1, pp. 3770. https://doi.org/10.1038/s41598-022-07630-5
  54. Yang D., Dai Y., Liu J., Zhou Y., Chen Y., Li C., Ma P., Lin J. Ultra-small BaGdF5-based upconversion nanoparticles as drug carriers and multimodal imaging probes. Biomaterials, 2014, vol. 35, no. 6, pp. 2011– 2023. https://doi.org/10.1016/j.biomaterials.2013.11.018
  55. Polukonova N. V., Isaev D. S., Myl’nikov A. M., Bucharskaya A. B., Polukonova A. V., Mudrak D. A., Navolokin N. A. Assessment by the Fluorescence Imaging Methods of the Antitumor Efficacy and Apoptotic Activity of Biologically Active Additives Containing Resveratrol, Indole-3-Carbinol, and Cordycepin in Human Renal Carcinoma Cells. Opt. Spectrosc., 2021, vol. 129, pp. 804–812 (in Russian). https://doi.org/10.1134/S0030400X21060114
  56. Myl’nikov A. M., Polukonova N. V., Isaev D. S., Doroshenko A. A., Verkhovskii R. A., Nikolaeva N. A., Mudrak D. A., Navolokin N. A. Identification of pathways of a498 human kidney carcinoma cell death under the action of gratiola officinalis l. extract and green tea flavonoids using fluorescence imaging techniques. Opt. Spectrosc., 2020, vol. 128, no. 7, pp. 972–979 (in Russian). https://doi.org/10.1134/S0030400X20070139
  57. Sagaidachnaya Е. А., Yanina I. Yu., Kochubey V. I. Prospects For Application of Upconversion Particles NaYF4:Er,Yb for Phototherapy. Izvestiya of Saratov University. Physics, 2018, vol. 18, no. 4, pp. 253–274 (in Russian). https://doi.org/10.18500/1817-3020-2018-18-4-253-274