title: Microbubbles and ultrasound increase intraventricular polyplex gene transfer to the brain.
abstract: 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® 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.
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA.
authors: James-Kevin Y
authors: JK
authors: Tan
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA.
authors: Binhan
authors: B
authors: Pham
authors: Center for Industrial and Medical Ultrasound, University of Washington, Seattle, WA 98195, USA; Department of Biomedical Engineering, Xian Jiaotong University, Xi'an, 710049, China.
authors: Yujin
authors: Y
authors: Zong
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Center for Industrial and Medical Ultrasound, University of Washington, Seattle, WA 98195, USA.
authors: Camilo
authors: C
authors: Perez
authors: Department of Neurological Surgery, University of Washington, Seattle, WA 98109, USA.
authors: Don O
authors: DO
authors: Maris
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA.
authors: Ashton
authors: A
authors: Hemphill
authors: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors: Carol H
authors: CH
authors: Miao
authors: Center for Industrial and Medical Ultrasound, University of Washington, Seattle, WA 98195, USA.
authors: Thomas J
authors: TJ
authors: Matula
authors: Department of Neurological Surgery, University of Washington, Seattle, WA 98109, USA.
authors: Pierre D
authors: PD
authors: Mourad
authors: Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors: Hua
authors: H
authors: Wei
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA.
authors: Drew L
authors: DL
authors: Sellers
authors: Department of Neurological Surgery, University of Washington, Seattle, WA 98109, USA. Electronic address: pjhorner@houstonmethodist.org.
authors: Philip J
authors: PJ
authors: Horner
authors: Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: spun@uw.edu.
authors: Suzie H
authors: SH
authors: Pun
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002412:Cations; D002460:Cell Line; D002831:Choroid Plexus / Q000166:cytology; D016503:Drug Delivery Systems; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007276:Injections, Intraventricular; D008810:Mice, Inbred C57BL; D045423:Microbubbles / Q000627:therapeutic use*; D010539:Permeability; D013499:Surface Properties; D000069453:Ultrasonic Waves
chemical_list: D002412:Cations
keywords: Choroid plexus epithelium; Gene delivery; In vivo; Microbubble; Polyplex; Ultrasound