title: Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Deliveryin vivo.
abstract: In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB). While there were no differences between both MMB types concerning size and lentivirus binding, SO-Mag MMB exhibited superior characteristics regarding magnetic moment, magnetizability as well as transduction efficiency under static and flow conditionsin vitro. Focal disruption of lentiviral SO-Mag MMB by ultrasound within isolated vessels exposed to an external magnetic field decisively improved localized VEGF expression in aortic endotheliumex vivoand enhanced the angiogenic response. Using the same systemin vivo, we achieved a highly effective, site-specific lentiviral transgene expression in microvessels of the mouse dorsal skin after arterial injection. Thus, we established a novel lentiviral MMB technique, which has great potential towards site-directed vascular gene therapy.
authors.affiliation: Walter Brendel Centre of Experimental Medicine, BMC, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany.; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, Munich.
authors.forename: Yvonn
authors.initials: Y
authors.lastname: Heun
authors.affiliation: Institute of Pharmacology and Toxicology, Biomedical Center University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Staffan
authors.initials: S
authors.lastname: Hildebrand
authors.affiliation: Central Institute of Medical Engineering (IMETUM), Technical University Munich, Boltzmannstrasse 11, 85748 Garching, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Heidsieck
authors.affiliation: Central Institute of Medical Engineering (IMETUM), Technical University Munich, Boltzmannstrasse 11, 85748 Garching, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gleich
authors.affiliation: Institute of Experimental Oncology and Therapy Research, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Anton
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Marchioninistrasse 15, 81377 Munich, Germany.; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, 80336 Munich, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, 80336 Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Institute of Experimental Oncology and Therapy Research, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Mykhaylyk
authors.affiliation: Physikalisch-Technische Bundesanstalt, Abbestrasse 2-12, 10587 Berlin, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Eberbeck
authors.affiliation: Institute of Physiology I, Life&Brain Center, University Clinic Bonn, 53127 Bonn.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Institute of Pharmacology and Toxicology, Biomedical Center University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstrasse 1, 80336 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Woernle
authors.affiliation: Invasive Cardiology, Starnberg Community Hospital, Osswaldstrasse 1, 82319 Starnberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Krötz
authors.affiliation: Walter Brendel Centre of Experimental Medicine, BMC, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany.; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, Munich.; Munich cluster for systems neurology, (SyNergy) Munich.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
authors.affiliation: Walter Brendel Centre of Experimental Medicine, BMC, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany.; DZHK (German Center for Cardiovascular Research) partner site Munich Heart Alliance, Munich.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mannell
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects*; D016503:Drug Delivery Systems; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics*; D058185:Magnetite Nanoparticles / Q000008:administration & dosage*; D051379:Mice; D045423:Microbubbles
chemical_list: D058185:Magnetite Nanoparticles
keywords: VEGF; endothelial cells.; lentiviral gene delivery; magnetic microbubbles; magnetic targeting; ultrasound