In recent years, high atomic number nanoparticles (NPs) have emerged as promising radio-enhancer agents for cancer radiation therapy due to their unique properties. Multi-disciplinary studies have demonstrated the potential of NPs-based radio-sensitizers to improve cancer therapy and tumor control at cellular and molecular levels. However, studies have shown that the dose enhancement effect of the NPs depends on the beam energy, NPs type, NPs size, NPs concentration, cell lines, and NPs delivery system. It has been believed that radiation dose enhancement of NPs is due to the three main mechanisms, but the results of some simulation studies failed to comply well with the experimental findings. Thus, this study aimed to quantitatively evaluate the physical, chemical, and biological factors of the NPs. An organized search of PubMed/Medline, Embase, ProQuest, Scopus, Cochrane and Google Scholar was performed. In total, 77 articles were thoroughly reviewed and analyzed. The studies investigated 44 different cell lines through 70 in-vitro and 4 in-vivo studies. A total of 32 different types of single or core-shell NPs in different sizes and concentrations have been used in the studies.

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Introduction: The present study was done to assess the effect of molecularly-targeted core/shell of iron oxide/gold nanoparticles (Fe3O4@AuNPs) on tumor radiosensitization of SKBr-3 breast cancer cells. Methods: Human epidermal growth factor receptor-2 (HER-2)-targeted Fe3O4@AuNPs were synthesized by conjugating trastuzumab (TZ, Herceptin) to PEGylated (PEG)-Fe3O4@AuNPs (41.5 nm). First, the Fe3O4@Au core-shell NPs were decorated with PEG-SH to synthesize PEG-Fe3O4@AuNPs. Then, the TZ was reacted to OPSS-PEG-SVA to conjugate with the PEG-Fe3O4@AuNPs. As a result, structure, size and morphology of the developed NPs were assessed using Fourier-transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM), and ultraviolet-visible spectroscopy. The SKBr-3 cells were treated with different concentrations of TZ, Fe3O4@Au, and TZ-PEG-Fe3O4@AuNPs for irradiation at doses of 2, 4, and 8 Gy (from X-ray energy of 6 and 18 MV). Cytotoxicity was assessed by MTT assay, BrdU assay, and flow cytometry. Results: Results showed that the targeted TZ-PEG-Fe3O4@AuNPs significantly improved cell uptake. The cytotoxic effects of all the studied groups were increased in a higher concentration, radiation dose and energy-dependent manner. A combination of TZ, Fe3O4@Au, and TZ-PEG-Fe3O4@AuNPs with radiation reduced cell viability by 1.35 (P=0.021), 1.95 (P=0.024), and 1.15 (P=0.013) in comparison with 8 Gy dose of 18 MV radiation alone, respectively. These amounts were obtained as 1.27, 1.58, and 1.10 for 8 Gy dose of 6 MV irradiation, respectively. Conclusion: Radiosensitization of breast cancer to mega-voltage radiation therapy with TZ-PEG-Fe3O4@AuNPs was successfully obtained through an optimized therapeutic approach for molecular targeting of HER-2.

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