Bioavailability of orally administered small extracellular vesicles from bovine milk in C57BL/6J mice

Abstract

Small extracellular vesicles (sMEVs) from bovine milk are studied for delivering therapeutics. Here, we estimated sMEV bioavailability of an oral dose of sMEVs. Bovine sMEVs were labeled covalently with HiLyte^TM 750 (MEV-750) and administered by oral gavage to C57BL/6J mice. Plasma, urine, feces, and tissues were harvested at timed intervals for up to 24 h and fluorescence was assessed. Fecal excretion amounted to approximately 55% of the oral MEV-750 dose in males and females. The levels of MEV-750 peaked in the intestinal mucosa and plasma approximately 6 h after oral gavage and returned to baseline at time point 24 h. MEV-750 were detectable in peripheral tissues approximately 12 h after gavage. MEV-750 excretion in urine peaked approximately 6 h after oral gavage and returned to background levels after 24 h. Analysis by size exclusion chromatography suggested that HiLyte^TM detached from sMEVs in artificial gastric fluid but not in plasma, i.e., HiLyte^TM allows to estimate sMEV bioavailability with comparably high confidence. We conclude that the apparent bioavailability of sMEVs is 45%, and sMEVs are transported to peripheral tissues in C57BL/6J mice; excretion in feces and urine are the main routes of sMEV elimination.

Keywords: Drug delivery; Extracellular vesicles; Feces; Milk; Plasma; Tissue distribution; Urine.