Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain

JOURNAL OF CONTROLLED RELEASE

卷:231

Article; Proceedings Paper

Tan, James-Kevin Y.^1,2  Binhan Pham^1,2  Zong, Yujin^3,4  Perez, Camilo^1,3  Maris, Don O.⁵  Hemphill, Ashton^1,2  Miao, Carol H.⁶  Matula, Thomas J.³  Mourad, Pierre D.⁵  Wei, Hua⁷  Sellers, Drew L.^1,2  Horner, Philip J.⁵  Pun, Suzie H.^1,2 

[1] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

[2] Univ Washington, Mol Engn & Sci Inst, Seattle, WA 98195 USA

[3] Univ Washington, Ctr Ind & Med Ultrasound, Seattle, WA 98195 USA

[4] Xi An Jiao Tong Univ, Dept Biomed Engn, Xian 710049, Peoples R China

[5] Univ Washington, Dept Neurol Surg, Seattle, WA 98109 USA

[6] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[7] Lanzhou Univ, Dept Chem, Lanzhou 730000, Peoples R China

关键词: Gene delivery;    Microbubble;    Polyplex;    Ultrasound;    In vivo;    Choroid plexus epithelium;   

DOI  :  10.1016/j.jconrel.2016.02.003

来源: Elsevier

【 摘 要 】

Neurons in the brain can be damaged or lost from neurodegenerative disease, stroke, or traumatic injury. Although neurogenesis occurs in mammalian adult brains, the levels of natural neurogenesis are insufficient to restore function in these cases. Gene therapy has been pursued as a promising strategy to induce differentiation of neural progenitor cells into functional neurons. Non-viral vectors are a preferred method of gene transfer due to potential safety and manufacturing benefits but suffer from lower delivery efficiencies compared to viral vectors. Since the neural stem and progenitor cells reside in the subventricular zone of the brain, intraventricular injection has been used as an administration route for gene transfer to these cells. However, the choroid plexus epithelium remains an obstacle to delivery. Recently, transient disruption of the blood-brain barrier by microbubble-enhanced ultrasound has been used to successfully improve drug delivery to the brain after intravenous injection. In this work, we demonstrate that microbubble-enhanced ultrasound can similarly improve gene transfer to the subventricular zone after intraventricular injection. Microbubbles of different surface charges (neutral, slightly cationic, and cationic) were prepared, characterized by acoustic flow cytometry, and evaluated for their ability to increase the permeability of immortalized choroid plexus epithelium monolayers in vitro. Based on these results, slightly cationic microbubbles were evaluated for microbubble and ultrasound-mediated enhancement of non-viral gene transfer in vivo. When coupled with our previously reported gene delivery vehicles, the slightly cationic microbubbles significantly increased ultrasound-mediated transfection of the murine brain when compared to commercially available Definity (R) microbubbles. Temporary disruption of the choroid plexus by microbubble-enhanced ultrasound is therefore a viable way of enhancing gene delivery to the brain and merits further research. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

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