title: Tumor growth suppression by the combination of nanobubbles and ultrasound.
abstract: We previously developed novel liposomal nanobubbles (Bubble liposomes [BL]) that oscillate and collapse in an ultrasound field, generating heat and shock waves. We aimed to investigate the feasibility of cancer therapy using the combination of BL and ultrasound. In addition, we investigated the anti-tumor mechanism of this cancer therapy. Colon-26 cells were inoculated into the flank of BALB/c mice to induce tumors. After 8 days, BL or saline was intratumorally injected, followed by transdermal ultrasound exposure of tumor tissue (1 MHz, 0-4 W/cm2 , 2 min). The anti-tumor effects were evaluated by histology (necrosis) and tumor growth. In vivo cell depletion assays were performed to identify the immune cells responsible for anti-tumor effects. Tumor temperatures were significantly higher when treated with BL + ultrasound than ultrasound alone. Intratumoral BL caused extensive tissue necrosis at 3-4 W/cm2 of ultrasound exposure. In addition, BL + ultrasound significantly suppressed tumor growth at 2-4 W/cm2 . In vivo depletion of CD8+ T cells (not NK or CD4+ T cells) completely blocked the effect of BL + ultrasound on tumor growth. These data suggest that CD8+ T cells play a critical role in tumor growth suppression. Finally, we concluded that BL + ultrasound, which can prime the anti-tumor cellular immune system, may be an effective hyperthermia strategy for cancer treatment.
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Omata
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Nishiie
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Koshima
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shiono
authors.affiliation: Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sawaguchi
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Johan
authors.initials: J
authors.lastname: Unga
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Naoi
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Department of Pharmaceutical Informatics, Department of Clinical Pharmacy, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawakami
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.|Institute of Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
authors.affiliation: Laboratory of Drug Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006979:Hyperthermia, Induced; D007111:Immunity, Cellular; D008081:Liposomes; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D047368:Tumor Burden; D000069453:Ultrasonic Waves
chemical_list: D008081:Liposomes
keywords: Cancer immunity; cavitation; hyperthermia; nanobubbles; ultrasound