title: Enhancement of Blood-Brain Barrier Permeability and Delivery of Antisense Oligonucleotides or Plasmid DNA to the Brain by the Combination of Bubble Liposomes and High-Intensity Focused Ultrasound.
abstract: The blood-brain barrier (BBB) is a major obstacle that prevents therapeutic drugs or genes from being delivered to the central nervous system. Therefore, it is important to develop methods to enhance the permeability of the BBB. We have developed echo-contrast gas (C₃F₈) entrapping liposomes (Bubble liposomes, BLs) that can work as a gene delivery tool in combination with ultrasound (US) exposure. Here, we studied whether the permeability of the BBB can be enhanced by the combination of BLs and high-intensity focused ultrasound (HIFU). Mice were intravenously injected with Evans blue (EB). BLs were subsequently injected, and the right hemispheres were exposed to HIFU. As a result, the accumulation of EB in the HIFU-exposed brain hemispheres was increased over that observed in the non-HIFU-exposed hemispheres, depending on the intensity and the duration of the HIFU. Similarly, the combination of BLs and HIFU allowed fluorescent-labeled antisense oligonucleotides to be delivered into the HIFU-exposed left hemispheres of the treated mice. Furthermore, a firefly luciferase-expressing plasmid DNA was delivered to the brain by the combination method of BLs and HIFU, which resulted in the increased gene expression in the brain at the focused-US exposure site. These results suggest that the method of combining BLs and HIFU together serves as a useful means for accelerating the permeability of BBB and thereby enabling antisense oligonucleotides or genes to be delivered to the focused brain site.
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. negishi@toyaku.ac.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Negishi
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. y091215@toyaku.ac.jp.
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamane
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. y104085@toyaku.ac.jp.
authors.forename: Naho
authors.initials: N
authors.lastname: Kurihara
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. endo@toyaku.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Endo-Takahashi
authors.affiliation: Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. y114099@toyaku.ac.jp.
authors.forename: Sanae
authors.initials: S
authors.lastname: Sashida
authors.affiliation: Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. takagino@toyaku.ac.jp.
authors.forename: Norio
authors.initials: N
authors.lastname: Takagi
authors.affiliation: Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. r-suzuki@pharm.teikyo-u.ac.jp.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. maruyama@pharm.teikyo-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
keywords: blood–brain barrier; bubble liposomes; nucleic acid delivery; ultrasound