title: Sonoprinting and the importance of microbubble loading for the ultrasound mediated cellular delivery of nanoparticles.
abstract: In the last years, research on ultrasound mediated drug delivery using microbubbles is vastly expanding. While some groups simply mix drugs and microbubbles (co-administration), other researchers have a major interest in the potential of drug-loaded microbubbles. However, today, little is known on the pros and cons of these two strategies. In this study we evaluated the delivery of nanoparticles (polystyrene nanospheres and mRNA-lipoplexes) to cells in vitro, in case the nanoparticles were mixed with unloaded microbubbles versus loaded onto the microbubbles. Flow cytometry experiments demonstrated that unloaded microbubbles did not enhance the cellular delivery of the nanospheres and mRNA-lipoplexes. However, upon loading the nanoparticles onto the microbubbles, their delivery to cells substantially improved. Real-time swept field confocal microscopy imaging of the microbubbles and cells during ultrasound radiation revealed that nanoparticle-loaded microbubbles directly deposited the nanoparticles in patches onto the cell membrane, a process that we termed 'sonoprinting'. This phenomenon resulted in the delivery of large amounts of nanoparticles to the cells and is suggested to be different from the creation of cell membrane pores and enhanced endocytosis, which have been reported before as mechanisms behind the improved delivery of drugs to cells by ultrasound.
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Ghent Research Group on Nanomedicine, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium. Electronic address: Ine.DeCock@UGent.be.
authors.forename: Ine
authors.initials: I
authors.lastname: De Cock
authors.affiliation: Physics of Fluids Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lajoinie
authors.affiliation: Physics of Fluids Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE, Enschede, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Ghent Research Group on Nanomedicine, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium. Electronic address: Stefaan.DeSmedt@UGent.be.
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Ghent Research Group on Nanomedicine, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium.
authors.forename: Ine
authors.initials: I
authors.lastname: Lentacker
mesh_terms: D045744:Cell Line, Tumor; D004705:Endocytosis; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D008055:Lipids / Q000737:chemistry; D045423:Microbubbles; D053758:Nanoparticles / Q000737:chemistry*; D054118:Nanospheres; D011137:Polystyrenes / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013010:Sonication / Q000379:methods*; D014465:Ultrasonics / Q000379:methods*
chemical_list: D008055:Lipids; D011137:Polystyrenes; D012333:RNA, Messenger
keywords: Drug delivery; Loaded microbubbles; Mechanisms; Microbubbles; Ultrasound