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Local delivery system of cytotoxic agents to tumors by focused sonoporation

Abstract

Recently, ultrasound-targeting microbubble destruction has been employed in molecular gene therapy, and a new potent nonviral gene transfer method known as ‘sonoporation’ has been developed. We investigated the efficiency of sonoporation toward growth inhibition of human gingival squamous carcinoma cell line, Ca9-22, in vitro and in vivo. The cytotoxicity of bleomycin (BLM) was investigated using flow-cytometric analysis and Hoechst's staining in vitro assay systems. We found that the delivery of BLM by sonoporation induced cytotoxic effect toward Ca9-22 cells in vitro. Our in vivo results showed that tumors nearly disappeared in Ca9-22 cell-implanted nude KSN/slc mice treated with a low dose of BLM followed by sonoporation during the 4-week experimental period. Histological analysis revealed that the cytotoxic effect was mainly apoptosis. We previously reported that the cytolethal distending toxin B (cdtB) from Actinobacillus actinomycetemcomitans, a periodontopathic bacterium, is responsible for cell cycle arrest and apoptosis in vitro. Thus, we used sonoporation to transfect a cdtB-expressing plasmid into Ca9-22 cells and examined cell viability in vitro and in vivo. We found that an administration of cdtB-expressing plasmid followed by sonoporation-induced marked growth inhibition of Ca9-22 cells and apoptotic cells were also observed in vitro and in vivo. These findings suggest that local administration of cytotoxic agents with sonoporation is a useful method for molecular cancer therapy.

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Acknowledgements

This work was supported in part by grants-in Aid from the Ministry of Education, Science and Culture of Japan and the Ministry of Health and Welfare of Japan.

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Correspondence to T Nishihara.

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Iwanaga, K., Tominaga, K., Yamamoto, K. et al. Local delivery system of cytotoxic agents to tumors by focused sonoporation. Cancer Gene Ther 14, 354–363 (2007). https://doi.org/10.1038/sj.cgt.7701026

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  • DOI: https://doi.org/10.1038/sj.cgt.7701026

Keywords

  • sonoporation
  • squamous cell carcinoma
  • apoptosis
  • in vivo transfection

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