Radiosensitizing effect of quercetin-encapsulated manganese dioxide nanoparticles on breast cancer cells

Abstract

Objective To investigate the radiosensitizating effect of quercetin (QU) loaded manganese dioxide nanoparticles [Mn(QU)] on breast cancer cell line 4T1 and tumour-bearing mice. Methods Manganese dioxide (MnO2) nanoparticles were synthesized by oleic acid template method. The morphology and chemical composition of MnO2 nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy. Then QU nanomaterials were encapsulated by using physical adsorption. The composition was characterized by ultraviolet spectrophotometer, and the ability of Mn(QU) nanoparticles reacting with different doses of hydrogen peroxide to produce oxygen at different pH values was detected by dissolved oxygen analyzer. CCK-8 assay was employed to detect the effects of different concentrations of Mn(QU) nanoparticles on the viability of 4T1 cells. Colony formation, γ-H2AX fluorescence staining, ROS fluorescence staining, LIVE/DEAD cell viability assay and flow cytometry were used to evaluate the radiosensitizing and pro-apoptotic effects of Mn(QU) nanoparticles on 4T1 cells. Finally, the effect of Mn(QU) nanoparticles combined with radiotherapy on tumor growth inhibition was evaluated in mouse model of 4T1 cell transplanted tumor. Results MnO2 nanoparticles with particle size of about 120 nm were successfully synthesized and encapsulated with QU. The oxygen generation capacity of the prepared Mn(QU) nanoparticles reacting with hydrogen peroxide was negatively correlated with pH value and positively with hydrogen peroxide concentration. The results of cell experiments showed that Mn(QU) nanoparticles at a concentration of 50 μg/mL had no obvious toxicity to 4T1 cells, but could significantly enhance the X-ray-induced killing effect on 4T1 cells, at a radiotherapy sensitization ratio of 1.61, improve DNA double-strand breaks and ROS production, and induce apoptosis of 4T1 cells. The results of tumor xenograft model experiment indicated that the inhibition of tumor volume was Mn(QU) nanoparticles combined with radiotherapy>MnO2 nanoparticles combined radiotherapy>QU combined radiotherapy>Radiotherapy>Control. Conclusion Mn(QU) nanoparticles combined with radiotherapy can significantly inhibit the proliferation and show radiosensitization of breast cancer 4T1 cells, and also exert a significant inhibitory effect on the growth of the transplanted tumor.

Keywords

• manganese dioxide
• quercetin
• radiation sensitization
• breast cancer