Effect of Transferrin on Cellular Uptake or Expulsion of Titanium Dioxide Nanoparticles

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in photodynamic therapy (PDT) of cancer treatment as excellent regenerative photocatalysts. However, there are some challenges because of their poor dispersity. Transferrin (Tf) was tried to modify the surface of TiO2 NPs to reduce the aggregation, which further affected uptake and excretion on SMMC-7721 human liver cancer cells. Initially, TiO2 NPs modified with Tf (TiO2-Tf NPs) entered into the cells faster than the pure TiO2 NPs which remain attaching on the cell membrane after short-term co-incubation. Tf modification increased the rate and amount of cellular endocytosis. Both TiO2 NPs and TiO2 Tf NPs were observed in lysosomes after long-term co-incubation through clathrin-mediated endocytosis pathway. Expulsion of NPs was then observed and it was found that the exocytosis of TiO2-Tf NPs was fast in the first 24 h, and then slowed down gradually from 24 h to 144 h. Totally, existence of Tf decreased the exocytosis of TiO2 NPs. Furthermore, the differences of cytotoxicity and genotoxicity between TiO2 NPs and TiO2-Tf NPs show that surface-adsorbed Tf components provide some protection from the cytotoxic effect by reducing the production of intracellular ROS. TiO2-Tf NPs obviously affected cell cycle, indicating a significant G2/M phase cell cycle arrest. Our results offer a promising application of easily aggregated TiO2 NPs in the nanomedicine field.