title: A versatile method for the preparation of particle-loaded microbubbles for multimodality imaging and targeted drug delivery.
abstract: Microbubbles are currently in clinical use as ultrasound contrast agents and under active investigation as mediators of ultrasound therapy. To improve the theranostic potential of microbubbles, nanoparticles can be attached to the bubble shell for imaging, targeting and/or enhancement of acoustic response. Existing methods for fabricating particle-loaded bubbles, however, require the use of polymers, oil layers or chemical reactions for particle incorporation; embed/attach the particles that can reduce echogenicity; impair biocompatibility; and/or involve multiple processing steps. Here, we describe a simple method to embed nanoparticles in a phospholipid-coated microbubble formulation that overcomes these limitations. Magnetic nanoparticles are used to demonstrate the method with a range of different microbubble formulations. The size distribution and yield of microbubbles are shown to be unaffected by the addition of the particles. We further show that the microbubbles can be retained against flow using a permanent magnet, can be visualised by both ultrasound and magnetic resonance imaging (MRI) and can be used to transfect SH-SY5Y cells with fluorescent small interfering RNA under the application of a magnetic field and ultrasound field.
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Owen
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.|Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
authors.forename: Calum
authors.initials: C
authors.lastname: Crake
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Jeong Yu
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.|Faculty of Engineering and the Environment, University of Southampton, Southampton, UK.
authors.forename: Dario
authors.initials: D
authors.lastname: Carugo
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Estelle
authors.initials: E
authors.lastname: Beguin
authors.affiliation: Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Khrapitchev
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Browning
authors.affiliation: Cancer Research UK & Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Sibson
authors.affiliation: Institute of Biomedical Engineering, Department of Engineering Science, Old Road Campus Research Building, University of Oxford, Headington, Oxford, OX3 7DQ, UK. eleanor.stride@eng.ox.ac.uk.
authors.forename: Eleanor
authors.identifier: 0000-0003-3371-5929
authors.initials: E
authors.lastname: Stride
mesh_terms: D045744:Cell Line, Tumor; D003287:Contrast Media; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000008:administration & dosage; D006801:Humans; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D045423:Microbubbles; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D010316:Particle Size; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage; D014463:Ultrasonography
chemical_list: D003287:Contrast Media; D005456:Fluorescent Dyes; D058185:Magnetite Nanoparticles; D010743:Phospholipids; D034741:RNA, Small Interfering
keywords: Contrast agents; Drug delivery; Magnetic; Microbubbles; Targeting; Ultrasound