Particularly, cerium dioxide (CeO2), also known as ceria, has emerged as an interesting material in a wide variety of industrial, technological, and medical applications. Ceria can be synthesized with various morphologies, including rods, cubes, wires, tubes, and spheres.

Synthesis of Cerium dioxide

All reagents were analytical grade and were used without further purification before the synthesized process. In a typical synthesis, 500 mL distilled water and 50 mL alcohol were firstly mixed in a 1 L Schott Duran glass bottle, and then 2.1732 g Ce(NO3)3*7H2O, 1.5039 g urea were dissolved into the above mixed solution under stirring to form a homogeneous solution. The glass bottle was sealed with a polypropylene screwcap and placed into ina domestic microwave oven (Galanz WD900SL23-2, China). The system was treated for 30 min at 720 W (a longer time heat athigher power was prohibited and solution was limited in 0.67 L),then the bottle was cooled naturally to room temperature, and the white precipitate was centrifuged and washed with distilled water and alcohol three times each. Finally, the obtained precipitate was dried at 100 C overnight and then heated at 500 C for 8 h to form the final Cerium dioxide powder. A yield was found to be 82-94%.[1]

Cerium Dioxide for Alzheimer's Disease

Resveratrol (3,5,40-trihydroxystilbene, RES) is a natural plant pheromone with various active effects, including reducing inflammation, scavenging oxidative stress and immunomodulatory effects. Some studies have shown that it has a potential therapeutic effect on AD. However, due to the difficulty of dissolving RES in water, the clinical application and therapeutic efficiency of RES are limited by its low bioavailability and the presence of the blood–brain barrier (BBB). Therefore, we integrated RES into the manganese-doped Cerium dioxide nanoparticles (MC) to improve their bioavailability. Since the surface of BBB containing lactoferrin transporters, we chose to modify the surface of MC with lactoferrin (cerium dioxide nanoparticle) to carry the drug to the brain without interference from the BBB. In addition, the lactoferrin modification not only modulates the drug release rate of MC but also improves their biocompatibility. In this study, lactoferrin-functionalized manganese-doped Cerium dioxide nanoparticles loaded with resveratrol (cerium dioxide nanoparticle-RES) were prepared to treat AD. We conducted in vivo and in vitro studies to demonstrate the antioxidant and neuroprotective effects of cerium dioxide nanoparticle-RES and to explore its mechanism of action. This has important implications for the treatment of AD.[2]

After 8 weeks of administration, we assessed the spatial cognitive ability and memory capacity of the model mice using the Morris water maze. Compared with normal mice, mice with AD show significant deficits in spatial learning, memory, and cognitive abilities. As displayed, the swimming paths of the mice with AD are evenly dispersed in the four quadrants, whereas those of the mice in the RES, cerium dioxide nanoparticle, and cerium dioxide nanoparticle-RES groups are relatively concentrated in the target area. The results show that the distance to the platform is shortened to different degrees in the RES, cerium dioxide nanoparticle, and cerium dioxide nanoparticle-RES groups compared to that in the AD group. The distance shortening is most pronounced in the cerium dioxide nanoparticle-RES group, which is 3.7 times that in the AD group. In addition, the escape latency is significantly reduced in the RES, cerium dioxide nanoparticle, and cerium dioxide nanoparticle-RES groups and is lower in the cerium dioxide nanoparticle-RES group than in the AD group. After platform removal, the cerium dioxide nanoparticle-RES group exhibits a significantly higher platform crossover than the AD group. Nesting experiments further validated the therapeutic effects of cerium dioxide nanoparticle-RES. Owing to cognitive deficits, the mice with AD were unable to complete nesting and had lower nesting scores than the normal group. In contrast, all mice in the RES, cerium dioxide nanoparticle, and cerium dioxide nanoparticle-RES groups showed significantly improved nesting abilities, with the cerium dioxide nanoparticle-RES group showing the most significant improvement.

Biological activity of cerium dioxide nanoparticles

The observed absorbance spectral changes of BSA loaded with cerium oxide in near-ultraviolet range indicate the occurrence of conformational changes caused by cerium oxide interaction with BSA. From this picture one can see gradual increase of absorbance value with an increase in molar concentration of Cerium dioxide nanoparticles, which were added to molar albumin solution, as well as and the appearance of a second maximum in the wavelength range from 300 to 340?nm. It could be explained as follows: the loading of BSA molecule with Cerium dioxide nanoparticles induces the conformation changes in protein leading to the separation of globular parts of albumin molecule, and partial ?opening? of the protein molecular domain structure, wherein two tryptophan residues and some of tyrosine residues, which initially were exposed to some internal hydrophobic surfaces, become accessible to solvent molecules of light source. It should be noted that no red or blue shift was observed for BSA during its loading by Cerium dioxide nanoparticles, which suggests the absence of dissociation process.[3]

The application of fluorescence spectroscopy is usually used to study the conformation of plasma proteins. The emission characteristics of aromatic amino acids residues such as tryptophan, tyrosine, and phenylalanine in protein can provide a convenient tool for investigation binding and conformation changes upon interaction with different substances including nanoparticles. The efficacy of fluorescence quenching is dependent on the proximity of quencher and the chromophore. Fluorescence, is largely attributed to the tryptophan residues of albumin. There is only a minor contribution by the more numerous tyrosines, and that is dependent on the wavelength of the exciting light. When this wavelength is between 295 and 305?nm, tyrosines are not excited, and only a pure tryptophan emission spectrum centered near 345?nm takes place. One of two tryptophans of BSA is in position 214 (Trp-214, loop 4) and the second one, Trp-134 is in loop 3 (Otosu, Nishimoto, & Yamashita, 2010). According to Carter and Ho (Carter  Ho, 1994) Trp-214 can be visualized in the pocket of subdomain IIA.;

The antioxidant defense system in organism includes various molecular factors that can prevent the formation of free radicals, initiate chain reactions, and eliminate already formed substances of this nature. At nanoscale, a large surface area of Cerium dioxide nanoparticles leads to formation of more Ce3+ as a result of ease formation of oxygen vacancies, and a free-radical scavenging property of Cerium dioxide nanoparticles has been also attributed to the presence of oxygen vacancies. Very recently we obtained very promising results confirmed the antioxidant defense of cardiomyocytes by Cerium dioxide nanoparticles in conditions of cardiomyopathy in rats with Walker 256 carcinosarcoma on the ninth day after tumor cells transplantation (the manuscript with detailed description of these data is in preparation). The impact of cerium nanoparticles causes an increase in the degree of cell spreading, the number of processes and contacts between cells, which indicates a decrease in the oncogenic potential of cells. The formation of intercellular contacts was also observed. Coloring cells revealed basophility, indicating on a decrease in the metabolic activity in the nuclei under the influence of cerium dioxide nanoparticles. The above morphofunctional features of the MCF-7 breast cancer cell line for cerium action indicate on a decrease in their oncogenic potential.

References

[1] Cheng, Cuixia; Chen, Fang; Yi, Huiyang; Lai, Guosong[Journal of Alloys and Compounds, 2017, vol. 694, p. 276 - 281]

[2] Hu, Y., Guo, H., Cheng, S., Sun, J., Du, J., Liu, X., Xiong, Y., Chen, L., Liu, C., Wu, C., & Tian, H. (2023). Functionalized Cerium Dioxide Nanoparticles with Antioxidative Neuroprotection for Alzheimer’s Disease. International Journal of Nanomedicine, 18, 6797 - 6812.

[3] Sarnatskaya, V., Shlapa, Y., Yushko, L., Shton, I., Solopan, S., Ostrovska, G., Kalachniuk, L., Negelia, A., Garmanchuk, L., Prokopenko, I. (2020). Biological activity of cerium dioxide nanoparticles. Journal of Biomedical Materials Research Part A, 108(8), 1703 - 1712.