An amplified sonodynamic therapy by a nanohybrid of titanium dioxide-gold-polyethylene glycol-curcumin: HeLa cancer cells treatment in 2D monolayer and 3D spheroid models

The utilization of ultrasound (US) to activate sonosensitizers for sonodynamic therapy (SDT) has faced challenges such as low activation efficiency and limited therapeutic outcomes, which have hampered its clinical applications. In this study, a nanohybrid of titanium dioxide-gold-polyethylene glycol-curcumin (TiO2-Au-PEG-Cur NH), as a novel US sensitizer, was synthesized, characterized, and applied for SDT of HeLa cancer cells in 2D monolayer model, and also a 3D spheroid model to bridge the gap between 2D cell culture and in vivo future studies. TiO2-Au-PEG-Cur NH contained TiO2 nanoparticles of 36 ± 11 nm in diameter, PEG-curcumin as a filler, and gold nanoparticles of 21 ± 7 nm in diameter with a high purity and a 35:17 of Ti:Au ratio (W/W), and it had a band gap of 2.4 eV, a zeta potential of –23 ± 7 mV, high stability upon US radiation cycles as well as one year storage. SDT of HeLa cells using TiO2-Au-PEG-Cur NH was investigated in the courses of cytotoxicity assessment in vitro, reactive oxygen species (ROS) generation capability, colony formation, cell migration, and the way to form spheroid. IC50 values of 122 and 38 μg mL−1 were obtained for TiO2-Au-PEG-Cur NH without and with US radiation, respectively. TiO2-Au-PEG-Cur NH not only exhibited an inherent capacity to generate ROS, but also represented an excellent therapeutic performance on the cancer cells through ROS generation and enhanced inhibitory effects on cell migration and spheroid formation.