Intracellular Drug Delivery with Anodic Titanium Dioxide Nanotubes and Nanocylinders

Titanium dioxide (TiO₂) holds remarkable promises for developing current theranostic strategies. Anodic TiO₂ nanostructures as a porous scaffold have offered a broad range of useful theranostic properties; however, previous attempts to generate single and uniform TiO₂ one-dimensional nanocarriers from anodic nanotube arrays have resulted in a broad cluster size distribution of arbitrarily broken tubes that are unsuitable for therapeutic delivery systems due to poor biodistribution and the risk of introducing tissue inflammation. Here, we achieve well-separated, uniformly shaped anodic TiO₂ nanotubes and nanocylinders through a time-varying electrochemical anodization protocol that leads to the generation of planar sheets of weakly connected nanotubes with a defined fracture point near the base. Subsequent sonication cleanly detaches the nanotubes from the base. Depending on the position of the fracture point, we can fabricate single-anodic nanocylinders that are open on both ends and nanotubes that are closed on one end. We proceed to show that anodic nanotubes and nanocylinders are nontoxic at therapeutic concentrations. When conjugated with the anticancer drug doxorubicin using a pH-responsive linker, they are readily internalized by cells and subsequently release their drug cargo into acidic intracellular compartments. Our results demonstrate that uniformly sized anodic TiO₂ nanotubes and nanocylinders are suitable for subcellular delivery of therapeutic agents in cancer therapy.