title: Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter.
abstract: Extracellular vesicles (EVs) are nanosized vesicles released by normal and diseased cells as a novel form of intercellular communication and can serve as an effective therapeutic vehicle for genes and drugs. Yet, much remains unknown about the in vivo properties of EVs such as tissue distribution, blood levels, and urine clearance, important parameters that will define their therapeutic effectiveness and potential toxicity. Here we combined Gaussia luciferase and metabolic biotinylation to create a sensitive EV reporter (EV-GlucB) for multimodal imaging in vivo, as well as monitoring of EV levels in the organs and biofluids ex vivo after administration of EVs. Bioluminescence and fluorescence-mediated tomography imaging on mice displayed a predominant localization of intravenously administered EVs in the spleen followed by the liver. Monitoring EV signal in the organs, blood, and urine further revealed that the EVs first undergo a rapid distribution phase followed by a longer elimination phase via hepatic and renal routes within six hours, which are both faster than previously reported using dye-labeled EVs. Moreover, we demonstrate systemically injected EVs can be delivered to tumor sites within an hour following injection. Altogether, we show the EVs are dynamically processed in vivo with accurate spatiotemporal resolution and target a number of normal organs as well as tumors with implications for disease pathology and therapeutic design.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lai
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Osama
authors.initials: O
authors.lastname: Mardini
authors.affiliation: Conventional Electron Microscopy Core, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Maguire
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.|Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
mesh_terms: D000818:Animals; D017930:Genes, Reporter; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D064847:Multimodal Imaging; D014018:Tissue Distribution