Rational design of oxygen deficient TiO2-x nanoparticles conjugated with chlorin e6 (Ce6) for photoacoustic imaging-guided photothermal/photodynamic dual therapy of cancer

Oxygen deficient TiO2-x nanoparticles (NPs) have been recognized as a category of new-fashioned photothermal agents to offer safer PTT. However, the surface of TiO2-x NPs is deficient in free active groups or radicals to conjugate functional therapeutic molecules, which seriously impedes their in-depth development for versatile medical applications. In this study, surface activation of TiO2-x NPs was realized by the facile conjugation of (3-aminopropyl)triethoxysilane (APTES) through the formation of a stable Si-O-Ti bond, and photosensitizer chlorin e6 (Ce6) was successfully modified onto the TiO2-x NP surface and with a considerably high loading content. The resultant TiO2-x@APTES/Ce6 (TAC) NPs displayed decent biosafety, rapid tumor enrichment and outstanding performance in photoacoustic (PA) imaging. Taking advantage of the intense photo-absorption in the near-infrared (NIR) region and high dose of conjugated Ce6, a powerful antitumor effect was realized based on the combination of hyperthermia-induced cell ablation and cytotoxic reactive oxygen species (ROS)-triggered apoptosis both in vitro and in vivo. Moreover, PA imaging guidance was exceptionally useful for locating the tumor position and optimizing the treatment regimens. Apart from Ce6, this elaborate modification strategy for TiO2-x is believed to be universal for steadily binding more versatile therapeutic agents, which would definitely favor the development of multifunctional TiO2-x-based nanocomplexes for enhanced tumor treatment.