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. 2019 Jun 27;9:9309. doi: 10.1038/s41598-019-45797-6

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Spheroid organization and TiO₂ NPs internalization: (A1) SEM micrograph of spheroids in the control condition (without NPs); (A2) with 5 and (A3) 100 µg/ml TiO₂ NPs exposure for 72 hours. (B1–B6) Internalization and distribution of TiO₂ NPs in spheroids exposed to 100 µg/ml NPs; (B1) Scanning TEM (STEM) micrograph of the interior of the spheroids. (B2) Schematic illustration of the penetration behavior of TiO₂ NPs, (B3) STEM micrograph of the outer layers of the spheroid showing TiO₂ NPs in the space between cells, (B4) and in membrane-vesicle, (B5) high magnification of the membrane vesicle, (B6) STEM/EDS map of Ti-K X-ray line confirming the presence of TiO₂ NPs. Images are representative of four independent analysis.