Background: The use of nanomaterial-based radiosensitizers to improve the therapeutic ratio has gained attraction in radiotherapy. Increased radiotoxicity applied to the tumor region may result in an adverse impact on the unexposed normal cells to the radiation, a phenomenon known as Radiation-Induced Bystander Effect (RIBE). Objective: This study aimed to investigate the effect of Bi2S3@BSA Nanoparticles (NPs) as radiosensitizers on the enhancement of bystander response in non-irradiated cells. Methods: Lung carcinoma epithelial cells were exposed to 6 MV x-ray photons at different doses of 2 and 8 Gy, with and without Bi2S3@BSA NPs. The Irradiated Cells Conditioned Medium (ICCM) was collected and incubated with MCR-5 human fetal lung fibroblasts. Results: This study showed that ICCM collected from 2-Gy-irradiated A549 cells in the presence of Bi2S3@BSA NPs reduced the cell viability of MCR-5 Bystander cells more than ICCM collected from irradiated cells without NPs (p<0.05), whereas such a difference was not observed after 8-Gy radiation. The mRNA expression of the BAX and XPA genes, as well as the cell death rate in MCR-5 bystander cells, revealed that the Bi2S3@BSA NPs significantly improved bystander response at 2 Gy (p<0.05), but the efficacy was not statistically significant after 8 Gy Irradiation. Conclusions: The results indicated that the presence of NPs did not affect bystander response enhancement at higher concentrations. These findings highlighted the potential use of radiation-enhancing agents and their benefits in radiotherapy techniques with high doses per fraction.
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