Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio
- 5.2k Downloads
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.
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.
Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.
KEY WORDSblood–brain barrier brain cancer drug delivery exosome zebrafish
Research reported in this project was supported by the Maine Cancer Foundation Pilot Research Grant 2013, the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103423, and the Salisbury Cove Research Fund. The authors thank Drs. Michelle Goody and Carol Kim at the University of Maine for kind help on the zebrafish study.
- 2.Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery—a novel application for the mesenchymal stem cell. Biotechnol Adv. 2012.Google Scholar
- 4.Lakhaland S, Wood MJ. Exosome nanotechnology: an emerging paradigm shift in drug delivery: exploitation of exosome nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers. BioEssays News Rev Mol Cell Dev Biol. 2011;33:737–41.CrossRefGoogle Scholar
- 13.Morikawa A, Peereboom DM, Thorsheim HR, Samala R, Balyan R, Murphy CG, et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro-Oncol. 2014.Google Scholar
- 22.Yang T, Bantegui T, Pike K, Bloom R, Phipps R, Bai S. In vitro evaluation of optimized liposomes for delivery of small interfering RNA. J Liposome Res. 2014.Google Scholar
- 23.Westerfield M. The Zebrafish book: a guide for the laboratory use of zebrafish (Brachydanio rerio), University of Oregon Press, Eugene. Or.; 1993.Google Scholar
- 27.Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx J Am Soc Exp Neurother. 2005;2:3–14.Google Scholar