PurposeThe aim of this study was to investigate the potential of the synergetic triple therapeutic combination encompassing bismuth oxide nanoparticles (BiONPs), cisplatin (Cis), and high dose rate (HDR) brachytherapy with Ir-192 source in breast cancer and normal fibroblast cell line.MethodsIn vitro models of breast cancer cell lines (MCF-7, MDA-MB-231) and normal fibroblast cell line (NIH/3T3) were employed. Cellular localization and cytotoxicity studies were conducted prior to inspection on the radiosensitization effects and generation of reactive oxygen species (ROS) on three proposed radiosensitizers: BiONPs, Cis, and BiONPs-Cis combination (BC). The optimal, non-cytotoxic concentration of BiONPs (0.5 mM) and the 25% inhibitory concentration of Cis (1.30 µM) were applied. The radiosensitization effects were evaluated by using a 0.38 MeV Iridium-192 HDR brachytherapy source over a prescribed dose range of 0 Gy to 4 Gy.ResultsThe cellular localization of BiONPs was visualized by light microscopy and accumulation of the BiONPs within the vicinity of the nuclear membrane was observed. Quantification of the sensitization enhancement ratio extrapolated from the survival curves indicates radiosensitization effects for MCF-7 and MDA-MB-231 when treated with BiONPs, Cis, and BC. However, NIH/3T3 cells exhibited contradictive behavior as it only reacted towards the BC combination. Nonetheless, the MCF-7 cell line loaded with BC shows the highest SER of 4.29. ROS production analysis, on the other hand, shows that Cis and BC radiosensitizers generated the highest free radicals in comparison to BiONPs alone.ConclusionA BiONPs-Cis combination was unveiled as a novel approach that offers promising radiosensitization enhancement that will increase the efficiency of tumor control while preserving the normal tissue at a reduced dose. This data is the first precedent to prove the synergetic implication of BiONPs, Cis, and HDR brachytherapy that will be beneficial for future chemoradiotherapy strategies in cancer care.
Metal-based nanoparticles such as gold, silver, platinum, and bismuth have been widely investigated for radiotherapeutic application. Basic understanding of the cellular interaction of the nanoparticles with the biological materials is crucial to ensure future clinical use. In this study, the cytotoxicity, cellular uptake, and generation of reactive oxygen species (ROS) induced by BiONPs were investigated prior elucidating the feasibility of BiONPs for radiotherapy application using megavoltage photon and electron beams. The BiONPs of diameter sizes 60, 70, 80 and 90 nm at concentrations within a range of 0.5 to 0.00005 mMol/L were tested on MCF-7, MDA-MB-231, and NIH/3T3 cells lines. The cytotoxicity results exhibit minimal cell death constituting less than 20 % of mortality on average. The ROS generation by BiONPs alone is found to be negligible as the ROS levels were slightly lower and higher than 100% of positive control. The increment of cellular nanoparticles uptake from a range of 1.50 % to 34.10 % indicates that BiONPs were internalized and bound to the surface of the cells. Sequencing from the results, 60 nm BiONPs are found to be the most suitable to be applied as a radiosensitizer in radiotherapy. Sensitization enhancement ratio (SER) quantified on MCF-7 cells demonstrated the highest enhancement from the highest concentration of BiONPs with SER of 2.29 and 1.42, for 10 MV photon beam and 6 MeV electron beam, respectively. In contrast to ROS production without radiation, the ROS induced from radiotherapy beams were found to be dose-dependent and play significant roles in radiosensitization effect. In conclusion, BiONPs could improve clinical radiotherapy, and further radiobiological characterization is crucial for future clinical translation.
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