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. 2024 Dec 23;16(12):1627.
doi: 10.3390/pharmaceutics16121627.

Biomedical Application Prospects of Gadolinium Oxide Nanoparticles for Regenerative Medicine

Ekaterina V Silina  1 , Natalia E Manturova  2 , Elena L Chuvilina  3 , Akhmedali A Gasanov  3 , Olga I Andreeva  3 , Maksim A Pugachevskii  4 , Aleksey V Kochura  4 , Alexey A Kryukov  5 , Yulia G Suzdaltseva  6 , Victor A Stupin  2
Affiliations

Biomedical Application Prospects of Gadolinium Oxide Nanoparticles for Regenerative Medicine

Ekaterina V Silina et al. Pharmaceutics. .

Abstract

Background/objectives: The aim was to study the possibilities of biomedical application of gadolinium oxide nanoparticles (Gd2O3 NPs) synthesized under industrial conditions, and evaluate their physicochemical properties, redox activity, biological activity, and safety using different human cell lines.

Methods: The powder of Gd2O3 NPs was obtained by a process of thermal decomposition of gadolinium carbonate precipitated from nitrate solution, and was studied using transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, mass spectrometry, and scanning electron microscopy (SEM) with energy dispersive X-ray analyzer (EDX). The redox activity of different concentrations of Gd2O3 NPs was studied by the optical spectroscopy (OS) method in the photochemical degradation process of methylene blue dye upon irradiation with an optical source. Biological activity was studied on different human cell lines (keratinocytes, fibroblasts, mesenchymal stem cells (MSCs)) with evaluation of the effect of a wide range of Gd2O3 NP concentrations on metabolic and proliferative cellular activity (MTT test, direct cell counting, dead cell assessment, and visual assessment of cytoarchitectonics). The test of migration activity assessment on a model wound was performed on MSC culture.

Results: According to TEM data, the size of the NPs was in the range of 2-43 nm, with an average of 20 nm. XRD analysis revealed that the f Gd2O3 nanoparticles had a cubic structure (C-form) of Gd2O3 (Ia3)¯ with lattice parameter a = 10.79(9) Å. Raman spectroscopy showed that the f Gd2O3 nanoparticles had a high degree of crystallinity. By investigating the photooxidative degradation of methylene blue dye in the presence of f Gd2O3 NPs under red light irradiation, it was found that f Gd2O3 nanoparticles showed weak antioxidant activity, which depended on the particle content in the solution. At a concentration of 10-3 M, the highest antioxidant activity of f Gd2O3 nanoparticles was observed when the reaction rate constant of dye photodegradation decreased by 5.5% to 9.4 × 10-3 min-1. When the concentration of f Gd2O3 NPs in solution was increased to 10-2 M upon irradiation with a red light source, their antioxidant activity changed to pro-oxidant activity, accompanied by a 15% increase in the reaction rate of methylene blue degradation. Studies on cell lines showed a high level of safety and regenerative potential of Gd2O3 NPs, which stimulated fibroblast metabolism at a concentration of 10-3 M (27% enhancement), stimulated keratinocyte metabolism at concentrations of 10-3 M-10-5 M, and enhanced keratinocyte proliferation by an average of 35% at concentrations of 10-4 M. Furthermore, it accelerated the migration of MSCs, enhancing their proliferation, and promoting the healing of the model wound.

Conclusions: The results of the study demonstrated the safety and regenerative potential of redox-active Gd2O3 NPs towards different cell lines. This may be the basis for further research to develop nanomaterials based on Gd2O3 NPs for skin wound healing and in regenerative medicine generally.

Keywords: biomedicine; cytotoxicity; drug development; gadolinium oxide; nanogadolinium; nanomaterials; nanoparticles; regeneration.

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Conflict of interest statement

The authors declare no conflicts of interest. The funder (Sechenov University) was not involved in the study’s design, and did not affect its results. The «LANHIT» company did not sponsor this study and did not participate in the further instrumental analysis of the obtained materials that were not performed on the basis of LANHIT. LLC «LANHIT» company has been a manufacturer of high and special purity inorganic compounds since 1991, including rare earth metal compounds. E.L.C, A.A.G., and O.I.A. are affiliated with “LANHIT” Company. E.L.C. was responsible for study of the literature on the synthesis of gadolinium oxide nanoparticles, scientific substantiation of the choice of synthesis methodology, data curation and control over the obtained nanoparticles, and participation in writing the article in the part describing the synthesis. A.A.G., the chief technologist of the company, was responsible for the selection of synthesis methods, the technical side of the syntheses, model development of the technology and the transfer of the technology to an industrial basis, and writing the chemical part of the article. O.I.A. conducted the synthesis and assessed the physical characteristics of the obtained nanoparticles, and helped write the chemical part of the article. Besides, all instrumental studies were conducted within the framework of non-financial agreements (cooperation agreement) between the institutions indicated in the affiliation of the article independently of each other. In particular, there is a scientific cooperation agreement between I.M. Sechenov First Moscow State Medical University (Sechenov University), and LANHIT Company.

Figures

Figure 1
Figure 1
TEM images of powdered Gd2O3 NPs, obtained on a JEM-2100 microscope at accelerating voltage 200 kV: (a) overview image of agglomerate and (b) its electronogram; (c,d) enlarged image before visualization of separate nanoparticles with scale bar 100 nm–10 nm; (e) size distribution of Gd2O3 NPs.
Figure 2
Figure 2
Diffractogram of a sample of Gd2O3 powder. The upper graph represents the experimental curve with indexing of peaks by the corresponding planes from which the diffraction occurred. The lower graph represents the difference between the experimental and theoretical diffractograms.
Figure 3
Figure 3
Raman spectrum of Gd2O3 powder with identification of the main Raman active modes. Inset photoluminescence spectrum of the sample near the wavelength of excitation radiation with marked energy transitions due to the presence of Eu3+ ions in the crystal lattice of Gd2O3.
Figure 4
Figure 4
Images of Gd2O3 powder particles obtained by scanning electron microscopy (a) and elemental distribution maps: Gd (b), O (c), and Eu (d). The insets show the image of the agglomerate with increased Eu content.
Figure 5
Figure 5
Dependence of the photodegradation rate constant of methylene blue and its variation on the concentration of Gd2O3 NPs under red light irradiation. Dashed line shows (MB) methylene blue without addition of Gd2O3 NPs. The arrows indicate that both the blue dashed line (MB) and the orange solid line (MB+Gd2O3) belong to the left axis (k), and the gray solid line (Gd2O3) belongs to the right axis (–Δk).
Figure 6
Figure 6
Effect of different concentrations of Gd2O3 NPs on metabolic activity of human fibroblasts in MTT test (* difference from control at p < 0.001, Dunnett post hoc tests).
Figure 7
Figure 7
Effect of different concentrations of Gd2O3 NPs on proliferative activity of fibroblasts by direct cell counting using an automated cell counter (p = 0.142).
Figure 8
Figure 8
Human fibroblasts after 72 h incubation with different concentrations of Gd2O3 NPs compared to control, magnification ×20.
Figure 9
Figure 9
Effect of different concentrations of Gd2O3 NPs on metabolic activity of human keratinocytes (BJTERT cells) in MTT test (* difference from control at p < 0.001, Dunnett post hoc tests).
Figure 10
Figure 10
Effect of different concentrations of Gd2O3 NPs on proliferative activity of fibroblasts (HaCaT cell line) by direct cell counting using an automated cell counter (* difference from control at p < 0.001, Dunnett post hoc tests).
Figure 11
Figure 11
Human keratinocytes after 72 h incubation with different concentrations of Gd2O3 NPs compared to control, magnification ×20.
Figure 12
Figure 12
Effects of Gd2O3 on migration of MSCs in scratch wound healing assay. (a) Representative images demonstrate the differences in migratory activity between MSCs under intact conditions and upon the Gd2O3 treatment. Brightfield microscopy, magnification —40×. (b) Time-dependent quantification of % confluency in the scratch wound area (* reliability of differences at p < 0.05; t-test).
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