Glucosylated Hybrid TiO₂/Polymer Nanomaterials for Actively Targeted Sonodynamic Therapy of Cancer

Sonodynamic therapy (SDT) is an anti-cancer therapeutic strategy based on the generation of reactive oxygen species (ROS) upon local ultrasound (US) irradiation of sono-responsive molecules or nanomaterials that accumulate in the tumor. In this work, the sonodynamic efficiency of sono-responsive hybrid nanomaterials composed of amorphous titanium dioxide and an amphiphilic poly(ethylene oxide)-b-poly(propylene oxide) block copolymer is synthesized, fully characterized, and investigated both in vitro and in vivo. The modular and versatile synthetic pathway enables the control of the nanoparticle size between 30 and 300 nm (dynamic light scattering) and glucosylation of the surface for active targeting of tumors overexpressing glucose transporters. Studies on 2D and 3D rhabdomyosarcoma cell cultures reveal a statistically significant increase in the sonodynamic efficiency of glucosylated hybrid nanoparticles with respect to unmodified ones. Using a xenograft rhabdomyosarcoma murine model, it is demonstrated that by tuning the nanoparticle size and surface features, the tumor accumulation is increased by ten times compared to main off-target clearance organs such as the liver. Finally, the SDT of rhabdomyosarcoma-bearing mice is investigated with 50-nm glucosylated nanoparticles. Findings evidence a dramatic prolongation of the animal survival and tumor volumes 100 times smaller than those treated only with ultrasound or nanoparticles.