title: PBCA-based polymeric microbubbles for molecular imaging and drug delivery.
abstract: Microbubbles (MB) are routinely used as contrast agents for ultrasound (US) imaging. We describe different types of targeted and drug-loaded poly(n-butyl cyanoacrylate) (PBCA) MB, and demonstrate their suitability for multiple biomedical applications, including molecular US imaging and US-mediated drug delivery. Molecular imaging of angiogenic tumor blood vessels and inflamed atherosclerotic endothelium is performed by modifying the surface of PBCA MB with peptides and antibodies recognizing E-selectin and VCAM-1. Stable and inertial cavitation of PBCA MB enables sonoporation and permeabilization of blood vessels in tumors and in the brain, which can be employed for direct and indirect drug delivery. Direct drug delivery is based on US-induced release of (model) drug molecules from the MB shell. Indirect drug delivery refers to US- and MB-mediated enhancement of extravasation and penetration of co-administered drugs and drug delivery systems. These findings are in line with recently reported pioneering proof-of-principle studies showing the usefulness of (phospholipid) MB for molecular US imaging and sonoporation-enhanced drug delivery in patients. They aim to exemplify the potential and the broad applicability of combining MB with US to improve disease diagnosis and therapy.
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany; Department of Intensive Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Koczera
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Appold
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Mengjiao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Dasgupta
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Vertika
authors.initials: V
authors.lastname: Pathak
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3583 CG Utrecht, The Netherlands.
authors.forename: Tarun
authors.initials: T
authors.lastname: Ojha
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Stanley
authors.initials: S
authors.lastname: Fokong
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Zhuojun
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institute for Molecular Cardiovascular Research, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany; Department of Genetics and Cell Biology - Molecular Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van Zandvoort
authors.affiliation: Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Iranzo
authors.affiliation: DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forckenbeckstr. 50, 52056 Aachen, Germany.
authors.forename: Alexander J C
authors.initials: AJC
authors.lastname: Kuehne
authors.affiliation: DWI-Leibniz Institute for Interactive Materials, RWTH Aachen University, Forckenbeckstr. 50, 52056 Aachen, Germany.
authors.forename: Andrij
authors.initials: A
authors.lastname: Pich
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Department of Experimental Molecular Imaging (ExMI), Helmholtz Institute for Biomedical Engineering, University Hospital RWTH, Pauwelsstr. 30, 52074 Aachen, Germany; Department of Targeted Therapeutics, Institute for Biomedical Technology and Technical Medicine, University of Twente, PO Box 217, 7500 AE Enschede, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3583 CG Utrecht, The Netherlands. Electronic address: tlammers@ukaachen.de.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000737:chemistry; D001710:Biotin / Q000008:administration & dosage / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D003911:Dextrans / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D019040:E-Selectin / Q000276:immunology; D004659:Enbucrilate / Q000008:administration & dosage* / Q000737:chemistry; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D008297:Male; D008819:Mice, Nude; D045423:Microbubbles; D057054:Molecular Imaging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D012235:Rhodamines / Q000008:administration & dosage / Q000737:chemistry; D019809:Streptavidin / Q000008:administration & dosage / Q000737:chemistry; D000069453:Ultrasonic Waves; D014463:Ultrasonography; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology
chemical_list: D000906:Antibodies; D003911:Dextrans; D019040:E-Selectin; D005456:Fluorescent Dyes; D012235:Rhodamines; D019010:Vascular Cell Adhesion Molecule-1; C015219:fluorescein isothiocyanate dextran; D001710:Biotin; D019809:Streptavidin; D040301:Vascular Endothelial Growth Factor Receptor-2; D004659:Enbucrilate; D016650:Fluorescein-5-isothiocyanate; C029773:rhodamine B
keywords: Microbubbles; Nanomedicine; Sonoporation; Tumor targeting; Ultrasound