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Assessing the Cytotoxicity of TiO2−x Nanoparticles with a Different Ti3+(Ti2+)/Ti4+ Ratio

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Abstract

Titanium dioxide (TiO2) nanoparticles are promising biomedical agents characterized by good biocompatibility. In this study, we explored the cytotoxicity of TiO2−x nanoparticles with a different Ti3+(Ti2+)/Ti4+ ratio and analyzed the efficiency of eryptosis indices as a tool in nanotoxicology. Two types of TiO2−x nanoparticles (NPs) were synthesized by the hydrolysis of titanium alkoxide varying the nitric acid content in the hydrolysis mixture. Transmission electron microscopy (TEM) images show that 1-TiO2−x and 2-TiO2−x NPs are 5 nm in size, whereas X-ray photoelectron spectroscopy (XPS) reveals different Ti3+ (Ti2+)/Ti4+ ratios in the crystal lattices of synthesized NPs. 1-TiO2−x nanoparticles contained 54% Ti4+, 38% Ti3+, and 8% Ti2+, while the relative amount of Ti4+ and Ti3+ in the crystal lattice of 2-TiO2−x nanoparticles was 63% and 37%, respectively. Cell viability and cell motility induced by TiO2−x nanoparticles were investigated on primary fibroblast cultures. Eryptosis modulation by the nanoparticles along with cell death mechanisms was studied on rat erythrocytes. We report that both TiO2−x nanoparticles do not decrease the viability of fibroblasts simultaneously stimulating cell migration. Data from in vitro studies on erythrocytes indicate that TiO2−x nanoparticles trigger eryptosis via ROS- (1-TiO2−x) and Ca2+-mediated mechanisms (both TiO2−x nanoparticles) suggesting that evaluation of eryptosis parameters is a more sensitive nanotoxicological approach for TiO2−x nanoparticles than cultured fibroblast assays. TiO2−x nanoparticles are characterized by low toxicity against fibroblasts, but they induce eryptosis, which is shown to be a promising tool for nanotoxicity screening. The Ti3+ (Ti2+)/Ti4+ ratio at least partly determines the cytotoxicity mechanisms for TiO2−x nanoparticles.

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Data Availability

Raw data were generated at Kharkiv National Medical University and Institute for Scintillation Materials of the National Academy of Sciences of Ukraine. Derived data that support the findings of this research are available from the corresponding author Anton Tkachenko on request.

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Acknowledgements

This study was performed as a fragment of a research entitled “Development of methods for evaluating biosafety and bioeffects of xenobiotics using in vitro and in vivo models.”

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Authors and Affiliations

  1. Research Institute of Experimental and Clinical Medicine, Kharkiv National Medical University, Kharkiv, 61022, Ukraine

    Volodymyr Prokopiuk, Anatolii Onishchenko & Anton Tkachenko

  2. Department of Cryobiochemistry, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Sciences of Ukraine, Kharkiv, 61015, Ukraine

    Volodymyr Prokopiuk

  3. Department of Nanostructured Materials, Institute for Scintillation Materials, National Academy of Sciences of Ukraine, Kharkiv, 61072, Ukraine

    Svetlana Yefimova, Pavel Maksimchuk & Irina Bespalova

  4. Department of Biochemistry, Kharkiv National Medical University, Kharkiv, 61022, Ukraine

    Anatolii Onishchenko & Anton Tkachenko

  5. Department of Internal and Occupational Diseases, Kharkiv National Medical University, Kharkiv, 61022, Ukraine

    Valeriy Kapustnik

  6. Department of Medical Biology, Kharkiv National Medical University, Kharkiv, 61022, Ukraine

    Valeriy Myasoedov

  7. Department of Phthisiology and Pulmonology, Kharkiv National Medical University, Kharkiv, 61022, Ukraine

    Dmytro Butov

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Contributions

All authors have made substantial contributions to this paper. Conceptualization: Anton Tkachenko, Anatolii Onishchenko; data analysis and original draft writing: Anton Tkachenko, Svetlana Yefimova, Volodymyr Prokopiuk; experimental data acquisition: Volodymyr Prokopiuk, Pavel Maksimchuk, Irina Bespalova, Antolii Onishchenko; interpretation of data: Anton Tkachenko, Svetlana Yefimova, Valeriy Kapustnik, Valeriy Myasoedov, Anatolii Onishchenko, Pavel Maksimchuk, Irina Bespalova; statistical analysis: Dmytro Butov, Volodymyr Prokopiuk; proofreading: Dmytro Butov, Anton Tkachenko, Svetlana Yefimova; funding: Anton Tkachenko, Valeriy Myasoedov, Valeriy Kapustnik. All authors read and approved the final version of manuscript.

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Correspondence to Anton Tkachenko.

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Prokopiuk, V., Yefimova, S., Onishchenko, A. et al. Assessing the Cytotoxicity of TiO2−x Nanoparticles with a Different Ti3+(Ti2+)/Ti4+ Ratio. Biol Trace Elem Res 201, 3117–3130 (2023). https://doi.org/10.1007/s12011-022-03403-3

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