Cytotoxicity, Retention, and Anti-inflammatory Effects of a CeO2 Nanoparticle-Based Supramolecular Complex in a 3D Liver Cell Culture Model

Christoph Eilenberger; Florian Selinger; Mario Rothbauer; Yiji Lin; Andreas Limbeck; Barbara Schädl; Johannes Grillari; Nataliya S Kavok; Vladimir K Klochkov; Yuri V Malyukin; Victor Margitich; Peter Ertl

doi:10.1021/acsptsci.0c00170

Cytotoxicity, Retention, and Anti-inflammatory Effects of a CeO₂ Nanoparticle-Based Supramolecular Complex in a 3D Liver Cell Culture Model

ACS Pharmacol Transl Sci. 2020 Dec 8;4(1):101-106. doi: 10.1021/acsptsci.0c00170. eCollection 2021 Feb 12.

Authors

Christoph Eilenberger^{1

2

3}, Florian Selinger^{1

2

3}, Mario Rothbauer^{1

2

3

4}, Yiji Lin¹, Andreas Limbeck¹, Barbara Schädl^{5

3}, Johannes Grillari^{5

3

6}, Nataliya S Kavok⁷, Vladimir K Klochkov⁷, Yuri V Malyukin⁷, Victor Margitich⁸, Peter Ertl^{1

2

3}

Affiliations

¹ Institute of Chemical Technologies and Analytics and Institute of Applied Synthetic Chemistry, Faculty of Technical Chemistry, Vienna University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
² SAICO Biosystems KG, Gumpendorferstraße 5/8, 1060 Vienna, Austria.
³ Austrian Cluster for Tissue Regeneration, Donaueschingenstraße 13, 1200 Vienna, Austria.
⁴ Medical University of Vienna, Department of Orthopedics and Trauma Surgery, Karl Chiari Lab for Orthopaedic Biology, Währingergürtel 18-19, 1090 Vienna, Austria.
⁵ Ludwig-Boltzmann-Institute for Experimental and Clinical Traumatology, Donaueschingenstraße 13, 1200 Vienna, Austria.
⁶ University of Natural Resources and Life Sciences, Dept. of Biotechnology, Institute for Molecular Biotechnology, Muthgasse 18, 1190 Vienna, Austria.
⁷ Institute for Scintillation Materials, STC "Institute for Single Crystals", 60 Science Avenue, 61001 Kharkiv, Ukraine.
⁸ Farmak JSC, 63, Kyrylivska Street, Kiev 04080, Ukraine.

Abstract

Both cerium oxide (CeOx) nanoparticles and mefenamic acid (MFA) are known anti-inflammatory agents with hepatoprotective properties and are therefore prescribed for one of the major diseases in the world, nonalcoholic fatty liver disease (NAFLD). To study the potential cytotoxicity and anti-inflammatory effects as well as drug retention of a potential therapeutic CeOx/MFA supramolecular complex, a well-standardized hepatic (HepG2) spheroid model was used. Results showed that the highest cytotoxicity for the CeOx/MFA supramolecular complex was found at 50 μg/mL, while effective doses of 0.1 and 1 μg/mL yielded a significant decrease of TNF-α and IL-8 secretion. Time-resolved analysis of HepG2 spheroids revealed a spatiotemporal distribution of the supramolecular complex and limited clearance from the internal microtissue over a period of 8 days in cultivation. In summary, our results point at rapid uptake, distribution, and biostability of the supramolecular complex within the HepG2 liver spheroid model as well as a significant anti-inflammatory response at noncytotoxic levels.