Hybrid amorphous titanium dioxide/polymeric nano-sonosensitizers towards the actively targeted sonodynamic therapy of brain cancer

This work investigates hybrid ceramic/polymeric sono-responsive nanomaterials made of amorphous titanium dioxide (aTiO₂) and a branched poly(ethylene oxide)-poly(propylene oxide) block copolymer surface-modified with the shuttle peptide cyclic Arg-Gly-Asp-d-Phe-Val that targets the αvβ3 integrin overexpressed in the blood-brain barrier endothelium and glioblastoma cells for the actively targeted sonodynamic therapy of brain cancer. The size of the nanoparticles is ∼100 nm, as measured by dynamic light scattering. Nanostructural analysis by high resolution-electron microscopies reveals that the nanoparticles consist of a porous aTiO₂ matrix with the polymeric amphiphile homogeneously incorporated in it. High-resolution X-ray photoelectron spectroscopy demonstrates the exposure of the shuttle peptide on the nanoparticle surface. The compatibility, uptake, and sonodynamic efficacy in vitro are studied in 2D and 3D cultures of the glioblastoma cell line U87. Results confirm the good cell compatibility of the nanoparticles and the contribution of the shuttle peptide to significantly increase their uptake and anticancer efficacy in vitro. Moreover, the shuttle peptide modification leads to a 6-fold increase in the nanoparticle accumulation in the brain and a sharp decrease in the accumulation in the liver of healthy mice upon one single intravenous injection, highlighting the promise of this platform for the targeted SDT of brain tumors.