title: Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption.
abstract: This study aimed to investigate the feasibility of targeted gene transfer into central nervous system (CNS) by MRI-guided focused ultrasound-induced blood-brain barrier (BBB) disruption. Before each sonication, T2-weighted images were obtained to select the target region. Followed by injecting DNA-loaded microbubbles into the tail vein, sonication was performed. The state of local BBB, distribution of plasmid DNA through the opened BBB, the ultrastructural changes of neurons and BDNF expression were detected. The results showed that MRI-guided focused ultrasound (FUS) could accomplish noninvasive, transient, and local BBB disruption, at 1h after sonication, plasmid DNA across the opened BBB had been internalized into the neurons presenting heterogeneous distribution and numerous transparent vesicles were observed in the cytoplasm of the neurons at the sonicated region, suggesting vesicle-mediated endocytosis. At 48 h after sonication, the expressions of exogenous gene pBDNF-EGFP were observed in the cytoplasm of some neurons, and BDNF expressions were markedly enhanced by the combination of ultrasound and pBDNF-EGFP-loaded microbubbles about 20-fold than that of the control group (P<0.01). The method by using MRI-guided FUS to induce the local BBB disruption could accomplish effective targeted exogenous gene transfer in CNS. This technique may provide a new option for the treatment of various CNS diseases.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: Jinmu
authors.initials: J
authors.lastname: Deng
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.forename: Yingjiang
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhibiao
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000293:injuries* / Q000502:physiology* / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D046529:Microscopy, Electron, Transmission; D013016:Sound / Q000009:adverse effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins