Modulation of tumour hypoxia by ultrasound-responsive microbubbles to enhance the sono-photodynamic therapy effect on triple-negative breast cancer

Sono-photodynamic therapy (SPDT) is an oxidative stress-dependant antitumour treatment modality. Due to the hypoxic tumour microenvironment, the antitumour effect of SPDT is limited. In this study, we developed lipid vesicles to transport a photosensitizer (chlorin e6, Ce6) and oxygen into tumours to promote SPDT efficiency on triple-negative breast cancer in vitro and in vivo. The results showed that compared with the same concentration of free Ce6, Lipo-Ce6 produced a higher singlet oxygen level under light irradiation. Cellular Lipo-Ce6 accumulation was 4-fold higher than that of free Ce6. The cytotoxicity on 4T1 cells caused by Lipo-Ce6-SPDT was significantly stronger than that caused by free Ce6-SPDT, and oxygen microbubbles (O2MB) further enhanced the cytotoxicity of Lipo-Ce6-SPDT under hypoxic conditions. Cellular ROS production in the Lipo-Ce6-SPDT+O2MB group was approximately 2.5-fold higher than that in the Lipo-Ce6-SPDT+C3F8MB group. Furthermore, O2MB rapidly relieved 4T1 subcutaneous xenograft hypoxia conditions under ultrasound exposure and significantly improved the antitumour activity of SPDT in vivo. These results indicate that the combination of O2MB and a high-activity liposome photosensitizer can significantly enhance the antitumour efficiency of SPDT for hypoxic tumours.