Encapsulation and Release of Doxorubicin from TiO2 Nanotubes: Experiment, Density Functional Theory Calculations, and Molecular Dynamics Simulation.

Titanium dioxide (TiO2) nanotubes are attractive materials for drug-delivery systems because of their biocompatibility, chemical stability, and simple preparation. In this study, we loaded TiO2 nanotubes with anticancer drug doxorubicin (DOX) experimentally and in all-atom molecular dynamics (MD) simulations. The release of doxorubicin from the nanotubes was studied by high-performance liquid chromatography (HPLC) and confocal Raman spectroscopy, and drug-release profiles were evaluated under various conditions. The polyethylene glycol (PEG) coating and capping of the nanotubes led to a marked increase in the water contact angles from about 16 to 33° in keeping with reduced wettability. The capping retarded the release rate without decreasing the overall release amount. The MD simulations further show that the DOX molecule diffusion coefficients (Di) are in the order of 10-10 m2/s. The DOX molecules show a plethora of short- and long-range H-bonding interactions with TiO2 nanotube walls and water. Calculated radial distribution functions (RDFs) and combined radial/angular distribution functions (CDFs) allowed gauging the strength of these hydrogen bonds. The strength does not fully correlate with the pKa values of DOX atoms which we assign to the confinement of DOX and water in the tubes. The lifetimes of hydrogen bonds between the DOX atoms and water molecules are shorter than that of the DOX...TiO2 interactions, and DOX...DOX aggregation does not play an important role. These results suggest TiO2 nanotubes as promising candidates for controllable drug-delivery systems for DOX or similar antiproliferative molecules.