Biodistribution, safety and toxicity profile of engineered extracellular vesicles

Background: The potential use of extracellular vesicles (EVs) as therapeutic carriers has attracted much interest with positive results in preclinical studies. Future development of EVs as delivery vectors requires in depth understanding of their general toxicity and biodistribution following in viv...

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Bibliographic Details
Published in:Journal of extracellular vesicles 2018-01, Vol.7, p.257-257
Main Authors: Lázaro-Ibáñez, Elisa, Saleh, Amer, Mairesse, Maelle, Rose, Jonathan, Harris, Jayne, Henderson, Neil, Shatnyeva, Olga, Osteikoetxea, Xabier, Heath, Nikki, Overman, Ross, Edmunds, Nicholas, Dekker, Niek
Format: Article
Language:English
Subjects:
Centrifugation
Cytokines
Disease transmission
Extracellular vesicles
Immunogenicity
Inflammation
Injection
Intravenous administration
Liver
Microscopy
Nanoparticles
Pharmacokinetics
Red fluorescent protein
Spleen
Toxicity
Transmission electron microscopy
Vectors
Western blotting
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Summary:Background: The potential use of extracellular vesicles (EVs) as therapeutic carriers has attracted much interest with positive results in preclinical studies. Future development of EVs as delivery vectors requires in depth understanding of their general toxicity and biodistribution following in vivo administration, particularly if EVs are derived from a xenogeneic source. Using human embryonic kidney cells EVs, we evaluated the general toxicity and compared different tracking methods to understand in vivo biodistribution of EVs in mice. Methods: EVs were generated from human wild type or transiently transfected Expi293F engineered cells to express reporter proteins, and isolated by differential centrifugation at 100K after removal of cell debris and larger EVs. Next, EVs were characterized by Western blotting, nanoparticle tracking analysis, transmission electron microscopy and fluorescent microscopy. To study EV-safety and toxicity, BALB/c mice were dosed with EVs by single intravenous (i.v.) injection, blood was collected to evaluate cytokine levels and haematology, and tissues were examined for histopathological changes. For biodistribution studies, red fluorescent protein and DiR-labelled EVs, or luminescent NanoLuclabelled EVs were i.v. injected in mice, and the tissue distribution and pharmacokinetics of EVs were evaluated using an in vivo imaging system (IVIS). Results: Administration of EVs in mice did not induce any significant toxicity with no gross or histopathological effects in the examined tissues 24 h after EV dosing. Moreover, there was no evidence of marked inflammatory cytokine induction. In vivo imaging showed that DiR-EV fluorescence signal was mainly detected in the liver and spleen with a relatively long retention time in the body (24 h), while red fluorescent protein-EVs produced a very weak signal mainly associated with the liver and spleen. On the other hand, luminescence signal derived from NanoLuc-labelled EVs was detected primarily in the lung with short retention time (1 h). Summary/Conclusion: This study shows that Expi293F-derived EVs do not induce significant toxicity or immunogenicity following single i.v. injection. These results also demonstrate that the use of engineered fluorescent/luminescent EVs is highly suitable to assess the in vivo EV biodistribution.
ISSN:2001-3078