We report on the use of nanobubbles (NB) with ultrasound (US) to permeabilize cancer cells and potentiate the cytotoxicity of anti-cancer drugs (cisplatin and 5-FU). We used 293T human kidney, MCF7 human breast adenocarcinoma, EMT6 murine mammary carcinoma and colon 26 murine rectum carcinoma cells. Cytotoxicity was evaluated with MTT assay. Under optimal conditions, NB (albumin or lipid, 10% v/v) combined with US (frequency: 945 kHz, duty ratio: 20-80%, pressure: 0.96 MPa) produced significant cytotoxicity not seen with either US or drug alone. Increasing the duty ratio up to 80% further increased cytotoxicity. From the observation of rapid collapse of nanobubbles with US, we hypothesised that sub-nanobubbles (cavitation bubbles) are produced by the collapse of nanobubbles and shock waves generated from the cavitation bubbles lead to the transient membrane permeability, followed by entry of plasmid DNA or drugs. To investigate the mechanisms of molecular delivery with shock waves, we performed molecular dynamics (MD) simulations of the interaction of the shock wave impulse with a lipid bilayer and subsequently increased the fluidity of each molecule of the layer. These changes in bilayer may be important factors to enhance drug susceptibility of cancer cells.
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