Site-specific sonocatalytic tumor suppression by chemically engineered single-crystalline mesoporous titanium dioxide sonosensitizers

Abstract

The biomedical applications of TiO₂-based nanosystems develop very slowly among diverse inorganic bio-nanosystems (e.g., Fe₃O₄, SiO₂, MnO, Au, etc.) due to the lack of adequate synthetic strategies to fabricate TiO₂ nanoparticles with desirable nanostructures and their specific light responses in the ultraviolet range with potential phototoxicity and low tissue-penetrating capability. In this work, we report on the rational design and fabrication of colloidal single-crystalline and mesoporous anatase TiO₂ nanoparticles (MTNs) with high dispersity, well-defined mesoporosity, uniform morphology and nanosized single-crystalline structure, employing a facile yet versatile bottom-up chemical strategy, i.e., pre-hydrolysis of titanium precursors combined with subsequent solvothermal treatment (PH-ST) simply using water as the additive. Highly biocompatible PEGylated MTNs have exerted their unique function as efficient sonosensitizers for sonodynamic therapy (SDT) of cancer, as systematically demonstrated both in vitro and in vivo. The production of reactive oxygen species (ROS) by MTN-sonosensitized SDT has been demonstrated to be the mechanism for efficient tumor SDT. The in vivo biocompatibility assay revealed that either a single dose at 150 mg kg⁻¹ or repeated doses at as high as a total of 400 mg kg⁻¹ exhibited no obvious in vivo toxicity. The ultrasound irradiation of MTNs in SDT is expected to break the depth shadow of light responsiveness of TiO₂-based nanosystems in the ultraviolet range, and the presence of well-defined mesoporous nanostructures of MTNs shows great potential for the delivery of therapeutic agents for combined cancer therapy.