Abstract
The gut microbial-derived metabolites of ellagitannins and ellagic acid, urolithins (Uros) are well-established anti-cancer metabolites according to preclinical studies. However, their efficacy is limited in systemic tissues, including the brain, by phase-II metabolism. Exosomes (EXOs), extracellular vesicles involved in cell signaling with the ability to cross the blood-brain barrier (BBB), could protect polyphenols from metabolism. Therefore, we loaded milk EXOs with Uro-A, Uro-B or IsoUro-A to evaluate their brain delivery and anticancer effects compared to non-encapsulated Uros. In Sprague-Dawley rats, perfused brain tissue analyses by UPLC-ESI-QTOF-MS showed higher Uro levels (∼3−4-fold) at 5 min following intravenous administration of EXO-Uros compared to non-encapsulated Uros, except for Uro-B, using similar Uro concentrations (17−30 μM). Experiments on neuroblastoma SH-SY5Y cells revealed dose-dependent antiproliferative effects for all EXO-Uros (0.3−1.2 μM), but not with non-encapsulated Uros (10 μM). Flow cytometry analyses indicated that only EXO-Uros arrested the cell cycle and induced apoptosis. Finally, using fluorescent-labeled EXOs and selective inhibitors, the primary endocytic pathway was revealed to be clathrin-dependent. Overall, encapsulating Uros into EXOs is promising for enhancing brain delivery and anticancer activity.
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