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Nanobubbles enhanced drug susceptibility of cancer cells using ultrasound
International Congress Series 1284 (2005) 338 – 339
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Nanobubbles enhanced drug susceptibility of cancer cells using ultrasound M. Suzuki a, K. Koshiyama b, F. Shinohara c, S. Mori c, M. Ono d, Y. Tomita e, T. Yano b, S. Fujikawa b, G. Vassaux f, T. Kodama a,* a
Tohoku University Biomedical Engineering Research Organization, Barts and The London School of Medicine and Dentistry, London, UK b Hokkaido University Graduate School of Engineering, Barts and The London School of Medicine and Dentistry, London, UK c Tohoku University Hospital, Barts and The London School of Medicine and Dentistry, London, UK d Tohoku University Graduate School of Medicine, Barts and The London School of Medicine and Dentistry, London, UK e Hokkaido University of Education Hakodate, Barts and The London School of Medicine and Dentistry, London, UK f Molecular Oncology Unit, Barts and The London School of Medicine and Dentistry, London, UK
Abstract. 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. D 2005 Published by Elsevier B.V. Keywords: Cancer; Nanobubble; Ultrasound; 5-FU; Cisplatin
* Corresponding author. 2-1 Seiryo-machi Aoba-ku Sendai 980-8575 Japan. Tel.: +81 22 717 7583; fax: +81 22 717 7583. E-mail address: [email protected] (T. Kodama). 0531-5131/ D 2005 Published by Elsevier B.V. doi:10.1016/j.ics.2005.06.090
M. Suzuki et al. / International Congress Series 1284 (2005) 338–339
339
1. Introduction Recently, destruction of nanobubbles (NB) mediated ultrasound (US) has been proposed as an innovative method for non-invasive and tissue-specific delivery of genes and drugs to the tissues of interest [1]. Several studies reported that this technique could be useful to overcome drug-resistance. In the present study, we demonstrated that the NB combined with US enhanced drug susceptibility of cancer cells in vitro. 2. Results and conclusions Four different cell lines were exposed to US under the optimized condition (frequency: 945 kHz, duty ratio: 50%, pressure: 0.96 MPa) with various concentrations of 5-FU or CDDP and cultured for 24 h. The cell viability was evaluated by MTT assay. The sensitivity of the cells to 5-FU (A) or CDDP (B) was effectively increased with NB and ultrasound (Fig. 1, *P b 0.05). The degree of the sensitivity depended on the cell type and the drug concentration. No significant cytotoxicity was seen with either US or drug alone. To investigate the mechanisms of drug delivery with NB, we performed molecular dynamics (MD) simulations [2] (Fig. 2). The interaction of the shock wave impulse with a lipid bilayer increased the fluidity of each molecule of the layer. These changes in bilayer may be important factors to enhance drug susceptibility of cancer cells.
References [1] T. Kodama, A.G. Doukas, M.R. Hamblin, Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves, Cancer Lett. 189 (1) (2003) 69 – 75. [2] K. Koshiyama, T. Kodama, M.R. Hamblin, A.G. Doukas, T. Yano, S. Fujikawa, Molecular delivery into a lipid bilayer with a single shock wave using molecular dynamics simulation, The 4th International Symposium on Therapeutic Ultrasound, 2004, 2004, Kyoto.
Fig. 1. Enhancement of drug susceptibility.
Fig. 2. Structural change in the lipid bilayer with a shock wave impulse. I p = 50 mPad s.
www.ics-elsevier.com
Nanobubbles enhanced drug susceptibility of cancer cells using ultrasound M. Suzuki a, K. Koshiyama b, F. Shinohara c, S. Mori c, M. Ono d, Y. Tomita e, T. Yano b, S. Fujikawa b, G. Vassaux f, T. Kodama a,* a
Tohoku University Biomedical Engineering Research Organization, Barts and The London School of Medicine and Dentistry, London, UK b Hokkaido University Graduate School of Engineering, Barts and The London School of Medicine and Dentistry, London, UK c Tohoku University Hospital, Barts and The London School of Medicine and Dentistry, London, UK d Tohoku University Graduate School of Medicine, Barts and The London School of Medicine and Dentistry, London, UK e Hokkaido University of Education Hakodate, Barts and The London School of Medicine and Dentistry, London, UK f Molecular Oncology Unit, Barts and The London School of Medicine and Dentistry, London, UK
Abstract. 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. D 2005 Published by Elsevier B.V. Keywords: Cancer; Nanobubble; Ultrasound; 5-FU; Cisplatin
* Corresponding author. 2-1 Seiryo-machi Aoba-ku Sendai 980-8575 Japan. Tel.: +81 22 717 7583; fax: +81 22 717 7583. E-mail address: [email protected] (T. Kodama). 0531-5131/ D 2005 Published by Elsevier B.V. doi:10.1016/j.ics.2005.06.090
M. Suzuki et al. / International Congress Series 1284 (2005) 338–339
339
1. Introduction Recently, destruction of nanobubbles (NB) mediated ultrasound (US) has been proposed as an innovative method for non-invasive and tissue-specific delivery of genes and drugs to the tissues of interest [1]. Several studies reported that this technique could be useful to overcome drug-resistance. In the present study, we demonstrated that the NB combined with US enhanced drug susceptibility of cancer cells in vitro. 2. Results and conclusions Four different cell lines were exposed to US under the optimized condition (frequency: 945 kHz, duty ratio: 50%, pressure: 0.96 MPa) with various concentrations of 5-FU or CDDP and cultured for 24 h. The cell viability was evaluated by MTT assay. The sensitivity of the cells to 5-FU (A) or CDDP (B) was effectively increased with NB and ultrasound (Fig. 1, *P b 0.05). The degree of the sensitivity depended on the cell type and the drug concentration. No significant cytotoxicity was seen with either US or drug alone. To investigate the mechanisms of drug delivery with NB, we performed molecular dynamics (MD) simulations [2] (Fig. 2). The interaction of the shock wave impulse with a lipid bilayer increased the fluidity of each molecule of the layer. These changes in bilayer may be important factors to enhance drug susceptibility of cancer cells.
References [1] T. Kodama, A.G. Doukas, M.R. Hamblin, Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves, Cancer Lett. 189 (1) (2003) 69 – 75. [2] K. Koshiyama, T. Kodama, M.R. Hamblin, A.G. Doukas, T. Yano, S. Fujikawa, Molecular delivery into a lipid bilayer with a single shock wave using molecular dynamics simulation, The 4th International Symposium on Therapeutic Ultrasound, 2004, 2004, Kyoto.
Fig. 1. Enhancement of drug susceptibility.
Fig. 2. Structural change in the lipid bilayer with a shock wave impulse. I p = 50 mPad s.