Development of tissue-selective gene delivery system ...

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Asian Journal of Pharmaceutical Sciences. Please cite this article ... School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan. *E-mail: ...
Accepted Manuscript Title: Development of tissue-selective gene delivery system with ultrasound Author: Ryo Suzuki, Daiki Omata, Yusuke Oda, Mutsumi Sugii, Hitoshi Uruga, Johan Unga, Yoichi Negishi, Sanae Oda, Kazuo Maruyama PII: DOI: Reference:

S1818-0876(15)00230-5 http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.067 AJPS 292

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Asian Journal of Pharmaceutical Sciences

Please cite this article as: Ryo Suzuki, Daiki Omata, Yusuke Oda, Mutsumi Sugii, Hitoshi Uruga, Johan Unga, Yoichi Negishi, Sanae Oda, Kazuo Maruyama, Development of tissue-selective gene delivery system with ultrasound, Asian Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Development of tissue-selective gene delivery system with ultrasound Ryo Suzukia,*, Daiki Omataa,b, Yusuke Odaa, Mutsumi Sugiia, Hitoshi Urugaa Johan Ungaa, Yoichi Negishic, Sanae Odaa, Kazuo Maruyamaa a

Faculty of Pharma-Scinces, Teikyo University, Tokyo, Japan, bJSPS Research Fellow

c

School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan

*E-mail: [email protected] Gene therapy is applied into cardiovascular diseases, cancer and diseases that are due to genomic causes. Viral vectors are efficient carriers of genes for transduction, but some problems have become evident. Delivery vectors that are highly potent in terms of gene transduction efficiency should also be safe and easy to apply. Non-viral vectors have recently received focus as gene carriers, but their transduction efficiency is very low and not suitable for in vivo gene delivery. In addition, it is important to develop tissue-specific or selective gene delivery system to avoid side effects in gene therapy. However, the gene delivery system which can easily change a transfection site has not been developed. Gene delivery with ultrasound is expected to be an attractive method for controlling gene delivery site due to induced driving force of gene transfection at the limited area where is insonated. In this study, we assessed the feasibility of tissue selective gene delivery with nanobubbles and ultrasound exposure. Gene delivery into liver or brain - Luciferase coded plasmid DNA (pCMV-Luc) (100 g) and nanobubbles (500 g) suspension was injected into tail vein of mice. Then, US was transdermally exposed to liver (frequency: 1 MHz, 1 W/cm2, 1 min) or transcranially exposed to brain (frequency: 1 MHz, 1.2 W/cm2, 1 min). After 1 day of injection, the luciferase expressions were measured.When ultrasound was exposed to liver, luciferase expression in liver was higher than that in other tissues (Fig. 1). On the other hand, when ultrasound was exposed to brain, luciferase expression was observed in brain. From these results, it was suggested that the tissue of gene delivery was controllable by changing the site of ultrasound exposure. In addition, we confirmed the gene expression cells in gene delivery for liver. In this case, gene expression was observed in parenchymal cells. Moreover, we also confirmed the parts of gene expression in brain after gene delivery. Gene expression was observed at wide area in brain. From these results, it is guessed that plasmid DNA might be extravasated with jet stream induced by cavitation of nanobubbles and delivered into parenchymal cells in liver and brain. Therefore, the combination of nanobubbles and ultrasound exposure would be a non-invasive and tissue selective gene delivery system.

Keywords: Ultrasound, Nanobubbles, Gene delivery

Acknowledgement

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

References [1] Suzuki R et al. Gene delivery by combination of novel liposomal bubbles with perfluoropropane and ultrasound. J Control Release. 117: 130-136 (2007) [2] Suzuki R, Oda Y, Utoguchi N, Maruyama K. Progress in the development of ultrasound-mediated gene delivery systems utilizing nano- and microbubbles. J Control Release. 149: 36-41 (2011)

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Luciferase activity (RLU/Organ)

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Liver

Kidney

Heart

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Spleen

Fig. 1. Luciferase expression with nanobubble and ultrasound exposure for liver

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