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, 14 (1), 328

Radiosensitizing Effect of Gadolinium Oxide Nanocrystals in NSCLC Cells Under Carbon Ion Irradiation

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Radiosensitizing Effect of Gadolinium Oxide Nanocrystals in NSCLC Cells Under Carbon Ion Irradiation

Feifei Li et al. Nanoscale Res Lett.

Abstract

Gadolinium-based nanomaterials can not only serve as contrast agents but also contribute to sensitization in the radiotherapy of cancers. Among radiotherapies, carbon ion irradiation is considered one of the superior approaches with unique physical and biological advantages. However, only a few metallic nanoparticles have been used to improve carbon ion irradiation. In this study, gadolinium oxide nanocrystals (GONs) were synthesized using a polyol method to decipher the radiosensitizing mechanisms in non-small cell lung cancer (NSCLC) cell lines irradiated by carbon ions. The sensitizer enhancement ratio at the 10% survival level was correlated with the concentration of Gd in NSCLC cells. GONs elicited an increase in hydroxyl radical production in a concentration-dependent manner, and the yield of reactive oxygen species increased obviously in irradiated cells, which led to DNA damage and cell cycle arrest. Apoptosis and cytostatic autophagy were also significantly induced by GONs under carbon ion irradiation. The GONs may serve as an effective theranostic material in carbon ion radiotherapy for NSCLC.

Keywords: Apoptosis; Carbon ion radiotherapy; Cytotoxic autophagy; DNA damage; Gadolinium oxide nanocrystals; Radiosensitizing effect.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The characteristics of the GONs. a HRTEM images of GONs. b EDS of GONs
Fig. 2
Fig. 2
The influence of GONs on hydroxyl radical production and cell survival fractions. a The dependence of hydroxyl radical production on the concentration of Gd after carbon ion irradiation. b–d The survival curve of GONs-pretreated A549 (b), NH1299 (c), and NH1650 (d) cells under carbon ion irradiation
Fig. 3
Fig. 3
GONs promoted ROS production. a The fluorescence images of ROS production observed after radiation by DCFH-DA, “CO” means the cotreatment with GONs and carbon ion radiation; scale bar represents 200 μm. b The relative fluorescence intensity of cells with or without GONs was analyzed using ImageJ software. *p < 0.05 or **p < 0.01 represent statistically significant or extremely significant differences, respectively
Fig. 4
Fig. 4
GONs enhanced the number of DNA double-strand breaks and extent of cell cycle arrest. a Fluorescent images of γ-H2AX foci in A549 cells were captured with a fluorescence microscope 2 h after radiation; scale bar is 20 μm; the nuclei stained with Hochest33342 are blue; the γ-H2AX foci visualized by incubating with fluorescent antibodies are red. b The numbers of foci per cell were counted over at least 50 cells. c The relative percentage of cells distributed in G2/M phase of cell cycle progression. *p < 0.05 or **p < 0.01 represent statistically significant or extremely significant differences, respectively
Fig. 5
Fig. 5
Marked apoptosis was induced by GONs in A549 and NH1650 cells but not in NH1299 cells. a The flow cytometry images indicating the apoptotic rates of A549 cells at 48 h after carbon ion radiation. b The relative incidence of apoptosis induced by GONs treatment and irradiation. *p < 0.05 or **p < 0.01 represent statistically significant or extremely significant differences, respectively, induced by GONs. Similarly, #p < 0.05 or ##p < 0.01 indicated significant or extremely significant differences, respectively, owing to radiation
Fig. 6
Fig. 6
Autophagy-induced death was promoted by GONs in NSCLC cells exposed to carbon ion irradiation. a Images of autophagic rates in A549 cells at 12 h post-radiation as measured by flow cytometry (Sysmex CyFlow Cube 6, German). b The relative incidence of autophagy in the three studied cell lines. c Western blot results of LC3II expression in the three studied cell lines. d The relative incidence of GONs-induced autophagy in the presence or absence of 3-MA. e The surviving A549 cells were dyed with crystal violet in the clonogenic survival assay. f Surviving fraction of NSCLC cells after treatment with 2 Gy carbon ion radiation and/ or GONs with or without 3-MA. *p < 0.05 or **p < 0.01 represent statistically significant or extremely significant differences, respectively, induced by GONs. Similarly, #p < 0.05 or ##p < 0.01 indicated the differences owing to 3-MA treatment

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