Platelet membrane-coated C-TiO2 hollow nanospheres for combined sonodynamic and alkyl-radical cancer therapy

The therapeutic efficiency of sonodynamic therapy (SDT) mainly depends on the presence of oxygen (O2) to generate harmful reactive oxygen species (ROS); thus, the hypoxic tumor microenvironment significantly limits the efficacy of SDT. Therefore, the development of oxygen-independent free radical generators and associated combination therapy tactics can be a promising field to facilitate the anticancer capability of SDT. In this study, a biomimetic drug delivery system (C-TiO2/AIPH@PM) composed of an alkyl-radical generator (2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride, AIPH)-loaded C-TiO2 hollow nanoshells (HNSs) as the inner cores, and a platelet membrane (PM) as the outer shells is successfully prepared for synergistic SDT and oxygen-independent alkyl-radical therapy. The PM encapsulation can significantly prolong the blood circulation time of C-TiO2/AIPH@PM compared with C-TiO2/AIPH while enabling C-TiO2/AIPH@PM to achieve tumor targeting. C-TiO2/AIPH@PM can efficiently produce ROS and alkyl radicals, which can achieve a more thorough tumor eradication regardless of the normoxic or hypoxic conditions. Furthermore, the generation of these radicals improves the efficiency of SDT. In addition, nitrogen (N2) produced due to the decomposition of AIPH enhances the acoustic cavitation effect and lowers the cavitation threshold, thereby enhancing the penetration of C-TiO2/AIPH@PM at the tumor sites. Both in vitro and in vivo experiments demonstrate that C-TiO2/AIPH@PM possesses good biosafety, ultrasound imaging performance, and excellent anticancer efficacy. This study provides a new strategy to achieve oxygen-independent free radical production and enhance therapeutic efficacy by combining SDT and free radical therapy.