Synergistic radiosensitization of breast cancer using bismuth oxide nanoparticles coated with chitosan and β-cyclodextrin loaded with curcumin and 5-aminolevulinic acid

Radiotherapy (RT) remains a cornerstone of Breast cancer (BC) treatment, but its effectiveness is hindered by challenges such as tumor hypoxia and lack of selectivity. Nanoparticles (NPs), especially those composed of high-Z materials like bismuth oxide (Bi₂O₃), have emerged as promising radiosensitizers to enhance RT efficacy. This study aims to compare the radiosensitizing effects of two functionalized Bi₂O₃-based NPs, chitosan (CS)-coated Bi₂O₃ NPs conjugated with 5-aminolevulinic acid and curcumin (Bi₂O₃/CS@5-ALA-CUR), and β-cyclodextrin (PCD)-coated Bi₂O₃ NPs conjugated with curcumin and glucose (Bi₂O₃@PCD-CUR-Glu), for targeted BC RT. Two Bi₂O₃-based NP formulations were synthesized and characterized for size, surface charge, and drug loading. Then, NPs were characterized fully. Their radiosensitizing effects were tested in-vitro using SKBr-3 and NIH3T3 cells, assessing cytotoxicity, reactive oxygen species (ROS) generation, and migration inhibition. In-vivo tumor growth inhibition was evaluated in a BALB/c mouse model with 6 MV X-rays (2 Gy) irradiation. Both NP formulations exhibited high biocompatibility and selective cytotoxicity towards SKBr-3 cells, reducing cell viability by 60–69% at 160 µg/mL. Bi₂O₃/CS@5-ALA-CUR NPs showed superior radiosensitization, reducing cell viability by 64% under 2 Gy irradiation. The functionalized NPs enhanced ROS generation, alleviated hypoxia (reducing hypoxic cell viability by 17%), and inhibited migration. In-vivo, Bi₂O₃/CS@5-ALA-CUR NPs combined with 2 Gy irradiation reduced tumor volume by 64%, compared to a 50% reduction with Bi₂O₃@PCD-CUR-Glu NPs. The study demonstrates that Bi₂O₃/CS@5-ALA-CUR NPs are more effective radiosensitizers than Bi₂O₃@PCD-CUR-Glu NPs in BC RT. These findings highlight the potential of modified Bi₂O₃ NPs in overcoming the limitations of traditional RT, providing a promising approach for improving treatment outcomes in BC.