Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio

Abstract

Purpose The blood–brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. Materials and Methods Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model. Results Four exosomes in 30–100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker. Conclusions Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.

Exosomes in cancer theranostic: Diamonds in the rough

“…93 In 2014, Pascucci et al showed that Mesenchymal Stem Cells (MSC) could incorporate and deliver Paclitaxel to recipient cells through exosomes with increased anti-tumor effects. 94 This study suggests that MSC-derived exosomes could be a new strategy for drug delivery in cancer treatment.…”

Therapeutic and diagnostic applications of extracellular vesicles

“…For hydrophobic membrane-permeable molecules, simple co-incubation at ambient or elevated temperature are often sufficient to load EVs [131,174]. Indeed, EVs derived from EL4 cells incubated with curcumin at room temperature were, after intranasal delivery, able to significantly delay brain tumor growth in the GL26 mice tumor model [137].…”

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