title: Ultrasound-targeted microbubble destruction-mediated gene delivery into canine livers.
abstract: Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics.
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors.forename: Misty L
authors.initials: ML
authors.lastname: Noble
authors.forename: Christian S
authors.initials: CS
authors.lastname: Kuhr
authors.forename: Scott S
authors.initials: SS
authors.lastname: Graves
authors.forename: Keith R
authors.initials: KR
authors.lastname: Loeb
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Sun
authors.forename: George W
authors.initials: GW
authors.lastname: Keilman
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Morrison
authors.forename: Marla
authors.initials: M
authors.lastname: Paun
authors.forename: Rainer F
authors.initials: RF
authors.lastname: Storb
authors.forename: Carol H
authors.initials: CH
authors.lastname: Miao
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics; D004285:Dogs; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008099:Liver / Q000378:metabolism*; D045423:Microbubbles; D010957:Plasmids; D011169:Portal Vein; D000637:Transaminases / Q000378:metabolism*; D014159:Transducers; D014162:Transfection / Q000379:methods*; D014464:Ultrasonic Therapy
chemical_list: D004247:DNA; D000637:Transaminases