Study of the mechanism of ultrasound-induced enhanced therapeutic effects of a chitosan-based nanoplatform.

Ultrasound has been used in drug delivery systems for controlling drug release and activation of ultrasound-sensitive drugs for sonodynamic therapy of cancer. In our previous work, we found that erlotinib-grafted chitosan nanocomplexes loading perfluorooctyl bromide and hematoporphyrin under ultrasound irradiation showed satisfactory therapeutic effects for non-small cell lung cancer treatment. However, the underlying mechanism of ultrasound-mediated delivery and therapy has not been fully explored. In this work, the underlying mechanisms of the ultrasound-induced effects of the nanocomplexes were evaluated at the physical and biological levels after the chitosan-based nanocomplexes were characterized. The results showed that ultrasound could activate the cavitation effects and promote nanocomplexes penetrating into the depth of three-dimensional multicellular tumor spheroids (3D MCTSs) when nanocomplexes were selectively uptaken by targeted cancer cells, but pushed the extracellular nanocomplexes out of the 3D MCTSs. Ultrasound demonstrated strong tissue penetration ability and effectively induce obvious reactive oxygen species production deep inside the 3D MCTSs. Under the ultrasound condition of 0.1 W/cm2 for 1 min, ultrasound caused little mechanical damage and weak thermal effect to avoid severe cell necrosis, whereas cell apoptosis could be induced by collapse of mitochondrial membrane potential and the nucleus damage. The present study indicates that ultrasound can potentially be used jointly with nanomedicine to improve targeted drug delivery and combination therapy of deep-seated tumors.