Ultrasmall Iron-Doped Titanium Oxide Nanodots for Enhanced Sonodynamic and Chemodynamic Cancer Therapy

Abstract Sonodynamic therapy (SDT), which can generate reactive oxygen species (ROS) based on sonosensitizers under ultrasound (US) to kill tumor cells, has emerged as a noninvasive therapeutic modality with high tissue-penetration depth. Herein, ultrasmall iron-doped titanium oxide nanodots (Fe-TiO2 NDs) are synthesized via a thermal decomposition strategy as a type of sonosensitizers to enhance SDT. Interestingly, the Fe doping in this system appears to be crucial in not only enhancing the US-triggered ROS generation of those NDs but also offering NDs the Fenton-catalytic function to generate ROS from tumor endogenous H2O2 for chemodynamic therapy (CDT). After polyethylene glycol (PEG) modification, Fe-TiO2-PEG NDs demonstrate good physiological stability and biocompatibility. With efficient tumor retention after intravenous injection as revealed by in vivo magnetic resonance (MR) and fluorescent imaging, our Fe-TiO2 NDs demonstrate much better in vivo therapeutic performance than commercial TiO2 nanoparticles owing to the combination of CDT and SDT. Moreover, most of those ultrasmall Fe-TiO2 NDs can be effectively excreted within one month, rendering no obvious long-term toxicity to the treated mice. Our work thus presents a type of multifunctional sonosensitizer for highly efficient cancer treatment via simply doping TiO2 nanostructures with metal ions.