title: Direct brain infusion can be enhanced with focused ultrasound and microbubbles.
abstract: The delivery of most therapeutic agents is rendered ineffective for the treatment of brain diseases due to the presence of the blood-brain barrier (BBB). The goal of this study was to investigate the effect of pre-infusion focused ultrasound (FUS) and microbubbles on the distribution of direct brain infusion in vivo. A single-element FUS transducer was used in all sonications, which were carried out immediately prior to direct infusion procedures. Mice received direct infusion of either Gadolinium-labeled albumin (Gd-albumin, 74 kDa) or adeno-associated virus (AAV, ∼4 MDa). The volumes of Gd-albumin at 30 min were deemed comparable ( P = 0.334) between the direct infusion (DI)-only group and the FUS + DI group. At 120 min, the FUS + DI group showed significantly higher contrast-enhanced volume (9.76 ± 0.74 mm3) than the DI-only group (7.14 ± 0.34 mm3). For mice infused with AAV, the total volume of transduction was estimated as GFP-positive regions and FUS + DI group demonstrated significantly higher ( P = 0.017) transduction efficiency in vivo. In conclusion, enhanced bio-distribution of directly infused agents was observed when the targeted region was pre-conditioned with FUS and microbubbles. Focused ultrasound has the potential, as an adjuvant technique, to significantly enhance direct brain infusion and achieve the desired therapeutic outcomes.
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Shutao
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Karakatsani
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Fung
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Acosta
authors.affiliation: 1 Department of Biomedical Engineering, Columbia University, New York, NY, USA.|2 Department of Radiology, Columbia University, New York, NY, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Konofagou
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003287:Contrast Media / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000229:Dependovirus / Q000235:genetics*; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005682:Gadolinium / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007260:Infusion Pumps; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013010:Sonication / Q000295:instrumentation; D014161:Transduction, Genetic
chemical_list: D003287:Contrast Media; D012709:Serum Albumin; D005682:Gadolinium
keywords: MRI; Ultrasound; gene therapy; microscopy; neurosurgery