Dual Action Enhancement of Gold Nanoparticle Radiosensitization by Pentamidine in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is an aggressive disease with a high risk of recurrence and death. Here, we present a novel strategy to enhance the radiotherapy of TNBC by combining gold nanoparticles (AuNPs) with pentamidine, a clinically approved anti-parasitic agent with anti-cancer properties. The radiosensitization effects of PEG-stabilized AuNPs (PEG-AuNPs) in combination with pentamidine were evaluated in two human TNBC cell lines (MDA-MB-231 and MDA-MB-436). Our results showed that PEG-AuNPs alone sensitized both cell lines to radiation, achieving dose enhancement factors of 1.26 and 1.15 in MDA-MB-231 and MDA-MB-436, respectively. In combination with pentamidine, the greatest dose enhancement was achieved in MDA-MB-231 after 24 h of treatment with 500 μM PEG-AuNPs and 20 μM pentamidine (dose enhancement factor of 1.55). Based on the in vitro data, it is projected that this combination would result in a 10 log increase in cell kill compared to radiation alone in a clinical setting, where 50 Gy is administered to breast cancer patients in 25 fractions over 5 weeks. Studies to elucidate the underlying mechanism of radiosensitization revealed that the adsorption of pentamidine onto the PEG-AuNP surface increased the cellular uptake of gold compared to PEG-AuNPs alone. In addition, the combination resulted in a significantly greater number of residual DNA double-strand breaks compared to that of either agent alone after a 2 Gy dose. Taken together, the dual action of pentamidine on the physical and biological pathways of radiosensitization by PEG-AuNPs results in superior radiotherapeutic effects of the combined treatment group in MDA-MB-231.