RESUMO
Ultrasound (US) has been used in drug delivery systems for controlling drug release and activation of US-sensitive drugs for sonodynamic therapy of cancer. In our previous work, we found that erlotinib-grafted chitosan nanocomplexes loading perfluorooctyl bromide and hematoporphyrin under US irradiation showed satisfactory therapeutic effects for non-small cell lung cancer treatment. However, the underlying mechanism of US-mediated delivery and therapy has not been fully explored. In this work, the underlying mechanisms of the US-induced effects of the nanocomplexes were evaluated at the physical and biological levels after the chitosan-based nanocomplexes were characterized. The results showed that US 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 push the extracellular nanocomplexes out of the 3D MCTSs. US demonstrated strong tissue penetration ability to effectively induce obvious reactive oxygen species production deep inside the 3D MCTSs. Under the US condition of 0.1 W cm-2for 1 min, US 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 US can potentially be used jointly with nanomedicine to improve targeted drug delivery and combination therapy of deep-seated tumors.