报告题目：Ultrasound Theranostics for Tumor

报告时间：2017年6月3日（周六）10:00-11:30

报告地点：南校区.第三教学楼C106教室

报 告 人：丸山一雄(日本帝京大学药学院)

主办单位：国际交流处

    药学院

    无涯学院

    研究生处（学科建设办公室）

    辽宁省研究生现代药物领域创新与交流中心

报告人简介：

Dr. Maruyama is a Professor of Laboratory of Drug Delivery Research, Faculty of Pharma-Sciences, Teikyo University.  He has graduated Graduate School of Pharmaceutical Sciences, Kumamoto University in 1979.  He studied PEG-immuno liposome in laboratory of Dr. Leaf Huang, University of Tennessee as Postdoctoral Research Associate on 1989-1991.  He has been full professor of Teikyo University since 2002.  He received the 1st MIZUSHIMA AWARD in The Japan Society of Drug Delivery System on Jun 28, 2009.  He is the Associate Editor of Journal of Liposome Research since 2002.  He had organized the 11th Liposome Research Days International Conference in Yokohama on July 19th, 2008. 

Recently, he has succeeded in developing a lipid bubble, which is a lipid micelle entrapping perfluorocarbon gas (perfluoropropane). Lipid bubble can use for both as a contrast agent in ultrasonography and a non-invasive carrier for drug and gene delivery.  When ultrasound irradiate lipid bubble, microstream or microjet occurs due to cavitation.Microstream or microjet result in shear stress to cells and the generation of transient pores in the cell membrane.  Drug and gene are introduced into cytoplasm directly by through this transient pores.  The combination of lipid bubble and ultrasound is a good tool for “Theranostics” in various diseases.

报告内容简介：

“Theranostics” is a treatment strategy that combines therapeutics with diagnostics. The combination of bubble formulation and ultrasound (US) is a good tool for “theranostics” due to have multi-potency both of diagnostics with enhanced echo signal from bubble and therapeutics with cavitation of bubble.  To develop a novel bubble formulation for US imaging and therapy with small particle size and a good stability and test the formulation as US imaging contrast agent and for gene delivery in vitro and in vivo.  Lipid-stabilized bubbles were prepared by homogenization of a lipid dispersion in the presence of perfluoropropane gas (Fig. 1).  Different phospholipid compositions were tested and evaluated. After bubble formation the bubbles were freeze-dried so that a dry sample containing bubbles was formed.  After re-constitution of the samples they were analyzed for size, gas content and US signal intensity.

The ultrasound theranostics capabilities of bubbles for the solid tumor were studied in Colon26 tumor bearing mice.  Bubbles was injected to mice via tail vein and 9 MHz linear ultrasound was exposed to solid tumor site transdermally.  The flow of bubbles in blood was observed and neovasculature of tumor tissue was imaged clearly (Fig. 2).  Following the recognition of neovasculature in tumor tissue, 1 MHz therapeutic ultrasound was exposed transdermally over the site of solid tumor tissue.  This process induced cavitation of bubbles in the tumor tissue, resulted in rising the temperature of tumor tissue to 45-55 ˚C, and also significant reduction of tumor growth.  Cavitation leads to localized heating and cloud be use for ablative cancer therapy. 

Interleukin-12 (IL-12) exhibits immunomodulatory antitumor effects and is considered an effective antitumor agent, but its short half-life and systemic toxicity following intravenous injection are major obstacles to its therapeutic use.  Therefore, we transfected pDNA encoding the IL-12 gene (pCMV-IL-12) into tumor tissue using bubbles and US with the aim of achieving high local expression of IL-12.  When pCMV-IL-12 was transfected using bubbles, US or Lipofectamine 2000, tumor growth was not suppressed. In contrast, transfection of pCMV-IL-12 with LBs and US suppressed tumor growth significantly (Fig. 3).  To investigate the mechanism behind the anti-tumor effects of pCMV-IL-12 transfected using bubbles and US, we assessed the involvement of CD4+ and CD8+ T cells and NK cells. The depletion of CD8+ T cells effectively blocked the anti-tumor effect of pCMV-IL-12 transfected using bubbles and US.  These results suggest that the combination of bubbles and US can effectively induce sufficient IL-12 expression to cause anti-tumor immune responses.

Thus, the combination of bubbles and US could be efficacious for neovasculature image and cancer therapy.  We believe this new formulation shows great promise for both diagnostic and therapeutic applications thanks to its good stability, relatively small bubble size and the simplicity of handling.

Acknowledgement：This study was supported by MEXT-Supported Program for the Strategic Research Foundation at Private Universities 2013-2017.