Effect of ROS generation on highly dispersed 4-layer O-TiO nanosheets toward tumor synergistic therapy.

Ultra-thin two-dimensional nanosheets have attracted increasing attention due to their great application prospects in nanomaterial science and biomedicine. Herein, we report the preparation of exfoliated raw and oxidized 4-layer TiO (O-TiO) and their ability to produce reactive oxygen species (ROS). The results show that O-TiO nanosheets can effectively produce ROS induced by X-ray irradiation. The 4-layer nanosheets can quickly load doxorubicin (DOX) within 5 min with a high loading rate to obtain a novel nanodrug system through their electrostatic adsorption capacity, and they exhibit a sustained release behavior. In this way, chemotherapy, radiation therapy and photodynamic therapy effectively combine for cancer synergistic treatment. We evaluated the cytotoxicity, cellular uptake and intracellular location of the O-TiO nanosheet-based drug delivery system in A549 lung cancer cells. Our results show that the O-TiO/DOX complex is more cytotoxic to A549 cells than free DOX since a low concentration of loaded DOX (10 μg/mL) with a low dose of X-rays can cause the complete apoptosis of tumor cells. This work reveals that the therapeutic effect of DOX-loaded O-TiO nanosheets is strongly dependent on their loading mode, and the effects of chemotherapy and photodynamic therapy are enhanced under X-ray irradiation, which allows O-TiO nanosheet use as a photo-activated drug carrier. This work provides a new strategy for preparing 2D metal oxide nanosheets toward biomedical applications.