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

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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.

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References

  1. Kooijmans SA, Vader P, van Dommelen SM, van Solinge WW, Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine. 2012;7:1525–41.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery—a novel application for the mesenchymal stem cell. Biotechnol Adv. 2012.

  3. van den Boorn JG, Dassler J, Coch C, Schlee M, Hartmann G. Exosomes as nucleic acid nanocarriers. Adv Drug Deliv Rev. 2013;65:331–5.

    Article  PubMed  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.

    Article  Google Scholar 

  5. Lai RC, Yeo RW, Tan KH, Lim SK. Exosomes for drug delivery—a novel application for the mesenchymal stem cell. Biotechnol Adv. 2013;31:543–51.

    Article  CAS  PubMed  Google Scholar 

  6. Gonzales PA, Pisitkun T, Hoffert JD, Tchapyjnikov D, Star RA, Kleta R, et al. Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol JASN. 2009;20:363–79.

    Article  CAS  Google Scholar 

  7. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29:341–5.

    Article  CAS  PubMed  Google Scholar 

  8. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano. 2013;7:7698–710.

    Article  CAS  PubMed  Google Scholar 

  9. Yangand J, Aschner M. Developmental aspects of blood-brain barrier (BBB) and rat brain endothelial (RBE4) cells as in vitro model for studies on chlorpyrifos transport. Neurotoxicology. 2003;24:741–5.

    Article  Google Scholar 

  10. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther J Am Soc Gene Ther. 2010;18:1606–14.

    Article  CAS  Google Scholar 

  11. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther J Am Soc Gene Ther. 2011;19:1769–79.

    Article  CAS  Google Scholar 

  12. Chenand Y, Liu L. Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev. 2012;64:640–65.

    Article  Google 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.

  14. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:5664–78.

    Article  CAS  Google Scholar 

  15. Muldoon LL, Soussain C, Jahnke K, Johanson C, Siegal T, Smith QR, et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:2295–305.

    Article  CAS  Google Scholar 

  16. Sathornsumeteeand S, Rich JN. New approaches to primary brain tumor treatment. Anti-Cancer Drugs. 2006;17:1003–16.

    Article  Google Scholar 

  17. Yang T, Nyiawung D, Silber A, Hao J, Lai L, Bai S. Comparative studies on chitosan and polylactic-co-glycolic acid incorporated nanoparticles of low molecular weight heparin. AAPS PharmSciTech. 2012;13:1309–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Bai S, Yang T, Abbruscato TJ, Ahsan F. Evaluation of human nasal RPMI 2650 cells grown at an air-liquid interface as a model for nasal drug transport studies. J Pharm Sci. 2008;97:1165–78.

    Article  CAS  PubMed  Google Scholar 

  19. Mittal A, Chitkara D, Kumar N. HPLC method for the determination of carboplatin and paclitaxel with cremophorEL in an amphiphilic polymer matrix. J Chromatogr B Anal Technol Biomed Life Sci. 2007;855:211–9.

    Article  CAS  Google Scholar 

  20. Iqbal T, Kinjo M, Dowling TC. Determination of Rhodamine 123 in cell lysate by HPLC with visible wavelength detection. J Chromatogr B Anal Technol Biomed Life Sci. 2005;814:259–62.

    Article  CAS  Google Scholar 

  21. Al-Abd AM, Kim NH, Song SC, Lee SJ, Kuh HJ. A simple HPLC method for doxorubicin in plasma and tissues of nude mice. Arch Pharm Res. 2009;32:605–11.

    Article  CAS  PubMed  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.

  23. Westerfield M. The Zebrafish book: a guide for the laboratory use of zebrafish (Brachydanio rerio), University of Oregon Press, Eugene. Or.; 1993.

  24. Jeong JY, Kwon HB, Ahn JC, Kang D, Kwon SH, Park JA, et al. Functional and developmental analysis of the blood-brain barrier in zebrafish. Brain Res Bull. 2008;75:619–28.

    Article  CAS  PubMed  Google Scholar 

  25. Yang XJ, Cui W, Gu A, Xu C, Yu SC, Li TT, et al. A novel zebrafish xenotransplantation model for study of glioma stem cell invasion. PLoS One. 2013;8:e61801.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Pardridge WM. Blood-brain barrier delivery. Drug Discov Today. 2007;12:54–61.

    Article  CAS  PubMed  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 

  28. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820:940–8.

    Article  CAS  PubMed  Google Scholar 

  29. Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011;81:1171–82.

    Article  CAS  PubMed  Google Scholar 

  30. Schneiderand A, Simons M. Exosomes: vesicular carriers for intercellular communication in neurodegenerative disorders. Cell Tissue Res. 2013;352:33–47.

    Article  Google Scholar 

  31. Simonsand M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21:575–81.

    Article  Google Scholar 

  32. Haqqani AS, Delaney CE, Tremblay TL, Sodja C, Sandhu JK, Stanimirovic DB. Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS. 2013;10:4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Taylorand DD, Gercel-Taylor C. Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol. 2011;33:441–54.

    Article  Google Scholar 

  34. De Rosa G, Salzano G, Caraglia M, Abbruzzese A. Nanotechnologies: a strategy to overcome blood-brain barrier. Curr Drug Metab. 2012;13:61–9.

    Article  PubMed  Google Scholar 

  35. Umansand RA, Taylor MR. Zebrafish as a model to study drug transporters at the blood-brain barrier. Clin Pharmacol Ther. 2012;92:567–70.

    Article  Google Scholar 

  36. Xie J, Farage E, Sugimoto M, Anand-Apte B. A novel transgenic zebrafish model for blood-brain and blood-retinal barrier development. BMC Dev Biol. 2010;10:76.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Basic Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor, Maine, 04401, USA

    Tianzhi Yang, Paige Martin, Brittany Fogarty, Alison Brown, Kayla Schurman, Roger Phipps & Shuhua Bai

  2. Davis Center for Regenerative Biology and Medicine,, Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, 04672, USA

    Viravuth P. Yin & Shuhua Bai

  3. Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia, 26506, USA

    Paul Lockman

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  1. Tianzhi Yang
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  2. Paige Martin
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  9. Shuhua Bai
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Correspondence to Shuhua Bai.

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Yang, T., Martin, P., Fogarty, B. et al. Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio . Pharm Res 32, 2003–2014 (2015). https://doi.org/10.1007/s11095-014-1593-y

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  • DOI: https://doi.org/10.1007/s11095-014-1593-y

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