RADIATION & RISK
Bulletin of the National Radiation and Epidemiological Registry
since 1992

Radiocatalytic properties of gadolinium-containing cerium oxide nanoparticles and their sensitizing effects on 3D-tumor cell spheroids

«Radiation and Risk», 2025, vol. 34, No. 4, pp.57-66

DOI: 10.21870/0131-3878-2025-34-4-57-66

Authors

Kolmanovich D.D. – Researcher
Chukavin N.N. – Researcher
Popov A.L. – Lead. Researcher, C. Sc., Biol. ITEB RAS. Contacts: 3 Institute str., Pushchino, Moscow region, Russia, 142290. Tel.: (4967)73-94-31; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
1 Institute of Theoretical and Experimental Biophysics of RAS, Pushchino
2 Federal State University of Education, Moscow

Abstract

Gadolinium (Gd)-based complexes are widely used in magnetic resonance imaging (MRI), however, their safety remains controversial. A key risk factor is the accumulation of gadolinium ions in healthy tissues upon repeated administration of these agents. Thus, there is an urgent need to develop new safe approaches for MRI imaging. One promising strategy involves nanoparticle-based formulations, which can minimize gadolinium ion release by retaining them within the crystal lattice. In this study, we developed cerium oxide nanoparticles doped with 10% and 20% (mol.) gadolinium (Ce0.8Gd0.1O2-х and Ce0.8Gd0.2O2-х, respectively). Their radiosensitizing properties were evaluated in a cell-free system and on 3D tumor cell spheroids. The nanoparticles containing 10% gadolinium exhibited pronounced radiocatalytic activity, whereas increasing the gadolinium content to 20% significantly reduced their radiosensitizing effects. pH-dependent radiation-induced activity of the nanoparticles was demon-strated. The most prominent reactive oxygen species (ROS) generation was observed at pH 6.5, while at pH 7.4, ROS production was notably lower. The combined action of Ce0.8Gd0.2O2- and X-ray irradiation suppressed the migratory activity of 4T1 and EMT6/P tumor cells in 3D spheroids. This effect may be attributed to enhanced ROS generation in the presence of the nanoparticles. The developed gadolinium-containing cerium oxide nanoparticles represent a promising theranostic agent for tumor diseases.

Key words
cerium oxide nanoparticles, gadolinium, radiosensitizers, radiocatalysis, 4T1 mouse ductal cancer cells, EMT6/P mouse breast cancer cells, 3D tumor spheroids, oncology, radiology.

References

1. Delaney G., Jacob S., Featherstone C., Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer, 2005, vol. 104, no. 6, pp. 1129-1137.

2. McBride W.H., Schaue D. Radiation-induced tissue damage and response. J. Pathol., 2020, vol. 250, no. 5, pp. 647-655.

3. Na H.B., Song I.C., Hyeon T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater., vol. 21, no. 21, pp. 2133-2148.

4. Bridot J.-L., Faure A.-C., Laurent S., Rivière C., Billotey C., Hiba B., Janier M., Josserand V., Coll J.-L., Elst L.V., Muller R., Roux S., Perriat P., Tillement O. Hybrid gadolinium oxide nanoparticles: multimodal contrast agents for in vivo imaging. J. Am. Chem. Soc., 2007, vol. 129, no. 16, pp. 5076-5084.

5. Mulder W.J., Strijkers G.J., van Tilborg G.A., Griffioen A.W., Nicolay K. Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging. NMR Biomed., 2006, vol. 19, no. 1, pp. 142-164.

6. Winter P.M., Morawski A.M., Caruthers S.D., Fuhrhop R.W., Zhang H., Williams T.A., Allen J.S., Lacy E.K., Robertson J.D., Lanza G.M., Wickline S.A. Molecular imaging of angiogenesis in early-stage atherosclerosis with alpha(v)beta3-integrin-targeted nanoparticles. Circulation, 2003, vol. 108, no. 18, pp. 2270-2274.

7. Celardo I., De Nicola M., Mandoli C., Pedersen J.Z., Traversa E., Ghibelli L. Ce3+ ions determine redox-dependent anti-apoptotic effect of cerium oxide nanoparticles. ACS Nano, 2011, vol. 5, no. 6, pp. 4537-4549.

8. Wu J., Wang X., Wang Q., Lou Z., Li S., Zhu Y., Qin L., Wei H. Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes (II). Chem. Soc. Rev., 2019, vol. 48, no. 4, pp. 1004-1076.

9. Chukavin N.N., Filippova K.O., Ermakov A.M., Karmanova E.E., Popova N.R., Anikina V.A., Ivanova O.S., Ivanov V.K., Popov A.L. Redox-active cerium fluoride nanoparticles selectively modulate cellular response against X-ray irradiation in vitro. Biomedicines, 2024, vol. 12, no. 1, pp. 11. DOI: 10.3390/biomedicines12010011.

10. Montini T., Melchionna M., Monai M., Fornasiero P. Fundamentals and catalytic applications of CeO2-based materials. Chem. Rev., 2016, vol. 116, no. 10, pp. 5987-6041.

11. Chukavin N.N., Ivanov V.K., Popov A.L. Calcein-modified CeO2 for intracellular ROS detection: mechanisms of action and cytotoxicity analysis in vitro. Cells, 2023, vol. 12, no. 19, pp. 2416. DOI: 10.3390/cells12192416.

12. Soni B., Makkar S., Biswas S. Effects of surface structure and defect behavior on the magnetic, electrical, and photocatalytic properties of Gd-doped CeO2 nanoparticles synthesized by a simple chemical process. Mater. Charact., 2021, vol. 174, pp. 110990. DOI: 10.1016/j.matchar.2021.110990.

13. Han X., Benkraouda M., Zhang Z., Amrane N. Oxygen vacancy diffusion and dynamics in Gd-doped CeO2: a GGA+U study. Solid State Commun., 2023, vol. 375, pp. 115359. DOI: 10.1016/j.ssc.2023.115359.

14. Wang S., Kobayashi T., Dokiya M., Hashimoto T. Electrical and ionic conductivity of Gd-doped ceria. J. Electrochem. Soc., 2000, vol. 147, no. 10, pp. 3606-3609.

15. Kolmanovich D.D., Chukavin N.N., Savintseva I.V., Mysina E.A., Popova N.R., Baranchikov A.E., Sozarukova M.M., Ivanov V.K., Popov A.L. Hybrid polyelectrolyte capsules loaded with gadolinium-doped cerium oxide nanoparticles as a biocompatible MRI agent for theranostic applications. Polymers, 2023, vol. 15, no. 18, pp. 3840. DOI: 10.3390/polym15183840.

16. Popov A.L., Abakumov M.A., Savintseva I.V., Ermakov A.M., Popova N.R., Ivanova O.S., Kolmanovich D.D., Baranchikov A.E., Ivanov V.K. Biocompatible dextran-coated gadolinium-doped cerium oxide nanoparticles as MRI contrast agents with high T1 relaxivity and selective cytotoxicity to cancer cells. J. Mater. Chem. B, 2021, vol. 9, no. 33, pp. 6586-6599.

17. Singh S., Dosani T., Karakoti A.S., Kumar A., Seal S. & Self W.T. A phosphate-dependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties. Biomaterials, 2011, vol. 32, no. 28, pp. 6745-6753.

18. Fares J., Fares M.Y., Khachfe H.H., Salhab H.A., Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct. Target. Ther., 2020, vol. 5, no. 1, pp. 28. DOI:10.1038/s41392-020-0134-x.

19. Faure A.C., Dufort S., Josserand V., Perriat P., Coll J.L., Roux S., Tillement O. Control of the in vivo biodistribution of hybrid nanoparticles with different poly (ethylene glycol) coatings. Small, 2009, vol. 5, no. 22, pp. 2565-2575.

20. Lux F., Sancey L., Bianchi A., Crémillieux Y., Roux S., illement O. Gadolinium-based nanoparticles for theranostic MRI-radiosensitization. Nanomedicine, 2015, vol. 10, no. 11, pp. 1801-1815.

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