Proton beam-induced radiosensitizing effect of Ce_0.8Gd_0.2O_2−x nanoparticles against melanoma cells in vitro

T Proton beam therapy is being used increasingly to treat melanoma. Meanwhile, proton beam therapy has a number of disadvantages that can be reduced or completely eliminated through the use of modern innovative approaches, including the use of nanoradiosensitizers. Here we showed the possibility of using redox-active dextran-stabilized Ce_0,8Gd_0,2O_2−x nanoparticles (Ce_0,8Gd_0,2O_2−x NPs) as a radiosensitizer to promote mouse melanoma cell death under proton beam irradiation in vitro. It has been shown that these Ce_0,8Gd_0,2O_2−x NPs do not reduce the viability and survival rate of both NCTC L929 normal mouse fibroblasts and B16/F10 mouse melanoma cells in a wide range of concentrations. However, Ce_0,8Gd_0,2O_2−x NPs significantly reduce the mitochondrial membrane potential of these cells. Additionally, it has been shown that Ce0,8Gd0,2O2−x NPs are able to effectively reduce the clonogenic activity of B16/F10 melanoma cells under proton beam irradiation. Meanwhile, proton beam irradiation remarkably reduced the clonogenic activity and MMP of melanoma cells. Hence, Ce_0,8Gd_0,2O_2−x NPs act as a radiosensitizer in B16/F10 mouse melanoma cells under proton beam irradiation. We assume that such radiosensitizing effect of Ce_0,8Gd_0,2O_2−x NPs is due to a decrease of the membrane mitochondrial potential. Thus, the use of Ce_0,8Gd_0,2O_2−x NPs in combination with proton beam irradiation is a promising approach for the effective treatment of melanoma.

1. Ringborg U., Bergqvist D., Brorsson B., Cavallin-stahl E., Ceberg J., Einhorn N., Fr ˙ odin J., J ¨ arhult J., Lamnevik G., Lindholm C., Littbrand B., ¨ Norlund A., Nylen U., Ros ´ en M., Svensson H., M ´ oller T. The Swedish Council on Technology Assessment in Health Care (SBU) Systematic ¨ Overview of Radiotherapy for Cancer Including a Prospective Survey of Radiotherapy Practice in Sweden 2001–Summary and Conclusions. Acta Oncol. 2003.

2. Baskar R., Lee K.A., Yeo R., Yeoh K.-W. Cancer and Radiation Therapy: Current Advances and Future Directions. Int. J. Med. Sci., 2012, 9, P. 193–199.

3. Yalamarty S.S.K., Filipczak N., Li X., Subhan M.A., Parveen F., Ataide J.A., Rajmalani B.A., Torchilin V.P. Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM). Cancers, 2023, 15, P. 2116.

4. Gregucci F., Beal K., Knisely J.P.S., Pagnini P., Fiorentino A., Bonzano E., Vanpouille-Box C.I., Cisse B., Pannullo S.C., Stieg P.E., et al. Biological Insights and Radiation–Immuno–Oncology Developments in Primary and Secondary Brain Tumors. Cancers, 2024, 16, P. 2047.

5. Mohan R. A Review of Proton Therapy – Current Status and Future Directions. Precis. Radiat. Oncol., 2022, 6, P. 164–176.

6. Chen, Z.; Dominello, M.M.; Joiner, M.C.; Burmeister, J.W. Proton versus Photon Radiation Therapy: A Clinical Review. Front. Oncol. 2023, 13.

7. Wang, H.; Mu, X.; He, H.; Zhang, X.-D. Cancer Radiosensitizers. Trends Pharmacol. Sci. 2018, 39, P. 24–48.

8. Gong, L.; Zhang, Y.; Liu, C.; Zhang, M.; Han, S.; Application of Radiosensitizers in Cancer Radiotherapy. Int J Nanomedicine. 2021, 16, P. 1083–1102. Erratum in: Int J Nanomedicine., 2021, 16, P. 8139–8140.

9. Varzandeh M., Sabouri L., Mansouri V., Gharibshahian M., Beheshtizadeh N., Hamblin M.R., Rezaei N. Application of Nano-Radiosensitizers in Combination Cancer Therapy. Bioeng. Transl. Med. 2023, 8, P. e10498.

10. Laurent S., Mahmoudi M. Superparamagnetic Iron Oxide Nanoparticles: Promises for Diagnosis and Treatment of Cancer. Int. J. Mol. Epidemiol. Genet., 2011, 2, P. 367–390.

11. Zavestovskaya I.N., Filimonova M.V., Popov A.L., Zelepukin I.V., Shemyakov A.E., Tikhonowski G.V., Savinov M., Filimonov A.S., Shitova A.A., Soldatova O.V., et al. Bismuth Nanoparticles-Enhanced Proton Therapy: Concept and Biological Assessment. Mater. Today Nano, 2024, 27, P. 100508.

12. Newhauser W.D., Zhang R. The Physics of Proton Therapy. Phys. Med. Biol., 2015, 60, P. R155.

13. Gerken L.R.H., Gogos A., Starsich F.H.L., David H., Gerdes M.E., Schiefer H., Psoroulas S., Meer D., Plasswilm L., Weber D.C., et al. Catalytic Activity Imperative for Nanoparticle Dose Enhancement in Photon and Proton Therapy. Nat. Commun., 2022, 13, P. 3248.

14. Wei H., Wang E. Nanomaterials with Enzyme-like Characteristics (Nanozymes): Next-Generation Artificial Enzymes. Chem. Soc. Rev., 2013, 42, P. 6060–6093.

15. 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, 48, P. 1004–1076.

16. Popov A.L., Shcherbakov A.B., Zholobak N.M., Baranchikov A.E., Ivanov V.K. Cerium Dioxide Nanoparticles as Third-Generation Enzymes (Nanozymes). Nanosyst. Phys. Chem. Math., 2017, P. 760–781.

17. Lin W., Huang Y., Zhou X.-D., Ma Y. Toxicity of Cerium Oxide Nanoparticles in Human Lung Cancer Cells. Int. J. Toxicol., 2006, 25, P. 451–457.

18. De Marzi L., Monaco A., De Lapuente J., Ramos D., Borras M., Di Gioacchino M., Santucci S., Poma A. Cytotoxicity and Genotoxicity of Ceria Nanoparticles on Different Cell Lines in Vitro. Int. J. Mol. Sci., 2013, 14, P. 3065–3077.

19. Wason M.S., Colon J., Das S., Seal S., Turkson J., Zhao J., Baker C.H. Sensitization of Pancreatic Cancer Cells to Radiation by Cerium Oxide Nanoparticle-Induced ROS Production. Nanomedicine Nanotechnol. Biol. Med., 2013, 9, P. 558–569.

20. 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, 15, P. 3840