Highly water-dispersible TiO2 nanoparticles for doxorubicin delivery: effect of loading mode on therapeutic efficacy

Highly water-dispersible titanium dioxide (TiO2) nanoparticles with abundant carboxyl groups were synthesized through a ligand exchange method. Chemotherapeutic doxorubicin (DOX) was then loaded on the TiO2 nanoparticles by non-covalent complexation (TiO2/DOX) or covalent conjugation (TiO2-DOX). The cytotoxicity, cellular uptake, and intracellular location of the two formulations were evaluated in C6 glioma cells. Our results showed that TiO2/DOX exhibited a greater cytotoxicity toward C6 cells than free DOX, while TiO2-DOX showed decreased cytotoxicity. A higher cellular uptake of TiO2-DOX was correlated with greater cytotoxicity of TiO2/DOX. In addition, confocal laser scanning microscopy demonstrated that most of the DOX was located inside the nuclei in TiO2/DOX. In contrast, TiO2-DOX was predominantly distributed in the cytoplasm. Thus, our work demonstrates that the therapeutic efficacy of TiO2-loaded DOX is strongly dependent on its loading mode and this provides important information for the future applications of TiO2 as a drug carrier.