Export file:

Format

  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text

Content

  • Citation Only
  • Citation and Abstract

Drug delivery application of extracellular vesicles; insight into production, drug loading, targeting, and pharmacokinetics

Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan

Extracellular vesicles (EVs) are secreted from any types of cells and shuttle between donor cells and recipient cells. Since EVs deliver their cargos such as proteins, nucleic acids, and other molecules for intercellular communication, they are considered as novel mode of drug delivery vesicles. EVs possess advantages such as inherent targeting ability and non-toxicity over conventional nanocarriers. Much efforts have so far been made for the application of EVs as a drug delivery carrier, however, basic techniques, such as mass-scale production, drug loading, and engineering of EVs are still limited. In this review, we summarize following four points. First, recent progress on the production method for EVs is described. Second, current techniques of drug loading methods are summarized. Third, targeting approach to specifically deliver cargo molecules for diseased sites by engineered EVs is discussed. Lastly, strategies to control pharmacokinetics and improve biodistribution are discussed.
  Figure/Table
  Supplementary
  Article Metrics

Keywords drug delivery system; drug loading; exosome; extracellular vesicle; gene therapy; microvesicle; nucleic acid therapeutics; pharmacokinetics; targeting

Citation: Masaharu Somiya, Yusuke Yoshioka, Takahiro Ochiya. Drug delivery application of extracellular vesicles; insight into production, drug loading, targeting, and pharmacokinetics. AIMS Bioengineering, 2017, 4(1): 73-92. doi: 10.3934/bioeng.2017.1.73

References

  • 1. Allen T M and Cullis P R (2004) Drug delivery systems: entering the mainstream. Science 303: 1818-1822.    
  • 2. Peer D, Karp J M, Hong S, et al. (2007) Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2: 751-760.    
  • 3. Choi H S, Liu W, Misra P, et al. (2007) Renal clearance of quantum dots. Nat Biotechnol 25: 1165-1170.    
  • 4. Matsumura Y and Maeda H (1986) A new concept for macromolecular therapeutics in cnacer chemotherapy: mechanism of tumoritropic accumulatio of proteins and the antitumor agents smancs. Cancer Res 46: 6387-6392.
  • 5. Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41: 189-207.    
  • 6. Bae Y H and Park K (2011) Targeted drug delivery to tumors: myths, reality and possibility. J Control Release 153: 198-205.    
  • 7. Wilhelm S, Tavares A J, Dai Q, et al. (2016) Analysis of nanoparticle delivery to tumours. Nat Rev Mater.1: 16014.
  • 8. Raposo G and Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200: 373-383.    
  • 9. Lener T, Gimona M, Aigner L, et al. (2015) Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper. J Extracell Vesicles 4: 41-31.
  • 10. Heijnen H F, Schiel A E, Fijnheer R, et al. (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94: 3791-3799.
  • 11. Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2: 569-579.
  • 12. Valadi H, Ekström K, Bossios A, et al. (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9: 654-659.    
  • 13. Gu H, Chen C, Hao X, et al. (2016) Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. J Clin Invest 126: 4537-4553.    
  • 14. Zomer A, Maynard C, Verweij F J, et al. (2015) In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161: 1046-1057.    
  • 15. Lai C P, Kim E Y, Badr C E, et al. (2015) Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat Commun 6: 7029.    
  • 16. Yamashita T, Takahashi Y, Nishikawa M, et al. (2016) Effect of exosome isolation methods on physicochemical properties of exosomes and clearance of exosomes from the blood circulation. Eur J Pharm Biopharm 98: 1-8.    
  • 17. Welton J L, Webber J P, Botos L, et al. (2015) Ready-made chromatography columns for extracellular vesicle isolation from plasma. J Extracell Vesicles 4: 1-9.
  • 18. Böing A N, Pol E, Grootemaat A E, et al. (2014) Single-step isolation of extracellular vesicles from plasma by size-exclusion chromatography. Int Meet Isev Rotterdam 3: 1-11.
  • 19. Nakai W, Yoshida T, Diez D, et al. (2016) A novel affinity-based method for the isolation of highly purified extracellular vesicles. Sci Rep 6: 33935.    
  • 20. Christianson H C, Svensson K J, Kuppevelt T H, et al. (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci.110: 17380.
  • 21 Balaj L, Atai N A, Chen W, et al. (2015) Heparin affinity purification of extracellular vesicles. Sci Rep 5: 10266.
  • 22. Munagala R, Aqil F, Jeyabalan J, et al. (2016) Bovine milk-derived exosomes for drug delivery. Cancer Lett 371: 48-61.    
  • 23 Watson D C, Bayik D, Srivatsan A, et al. (2016) Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials 105: 195-205.    
  • 24 Wahlgren J, Karlson T, Brisslert M, et al. (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40: e130.
  • 25 Wang Q, Zhuang X, Mu J, et al. (2013) Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat Commun 4: 1867.
  • 26 Zhang M, Viennois E, Prasad M, et al. (2016) Edible ginger-derived nanoparticles: a novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials 101: 321-340.    
  • 27 Wurm F M (2004) Production of recombinant protein therapeutics in cultivated mammalian cells. Nat Biotechnol 22: 1393-1398.    
  • 28 Pisitkun T, Shen R F, Knepper M A (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci 101: 13368-13373.    
  • 29 Record M (2013) Exosome-like nanoparticles from food: protective nanoshuttles for bioactive cargo. Mol Ther 21: 1294-1296.    
  • 30 Izumi H, Tsuda M, Sato Y, et al. (2015) Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. J Dairy Sci 98: 2920-2933.    
  • 31 Pieters B, Arntz O J, Bennink M B, et al. (2015) Commercial cow milk contains physically stable extracellular vesicles expressing immunoregulatory TGF-β. Plos One 10: e0121123.
  • 32 Kosaka N, Izumi H, Sekine K, et al. (2010) MicroRNA as a new immune-regulatory agent in breast milk. Silence 1: 7.
  • 33 Hata T, Murakami K, Nakatani H, et al. (2010) Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem Biophys Res Commun 396: 528-533.    
  • 34 Wolf T, Baier S R, Zempleni J (2015) The intestinal transport of bovine milk exosomes is mediated by endocytosis in human colon carcinoma Caco-2 cells and rat small intestinal Iec-6 cells. J Nutr 145: 2201-2206.    
  • 35 Baier S R, Nguyen C, Xie F, et al. (2014) MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J Nutr 144: 1495-1500.    
  • 36 Ju S, Mu J, Dokland T, et al. (2013) Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from dss-induced colitis. Mol Ther 21: 1345-1357.    
  • 37 Zhuang X, Teng Y, Samykutty A, et al. (2015) Grapefruit-derived nanovectors delivering therapeutic miR17 through an intranasal route inhibit brain tumor progression. Mol Ther 24: 96-105.
  • 38 Wang Q, Ren Y, Mu J, et al. (2015) Grapefruit-derived nanovectors use an activated leukocyte trafficking pathway to deliver therapeutic agents to inflammatory tumor sites. Cancer Res 75: 2520-2529.    
  • 39 Wang B, Zhuang X, Deng Z, et al. (2014) Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol Ther 22: 522-534.    
  • 40 Barenholz Y (2012) Doxil-the first fda-approved nano-drug: lessons learned. J Control Release 160: 117-134.    
  • 41 Kosaka N, Iguchi H, Yoshioka Y, et al. (2012) Competitive interactions of cancer cells and normal cells via secretory micrornas. J Biol Chem 287: 1397-1405.    
  • 42 Katsuda T, Tsuchiya R, Kosaka N, et al. (2013) Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep.3: 1197.
  • 43 Chevillet J R, Kang Q, Ruf I K, et al. (2014) Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc Natl Acad Sci 111: 14888-14893.
  • 44 Kosaka N, Iguchi H, Yoshioka Y, et al. (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285: 17442-17452.    
  • 45 Hagiwara K, Katsuda T, Gailhouste L, et al. (2015) Commitment of annexin A2 in recruitment of micrornas into extracellular vesicles. Febs Lett 589: 4071-4078.    
  • 46 Shurtleff M J, Temoche-Diaz M M, Karfilis K V, et al. (2016) Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. Elife 5: e19276.
  • 47 Yim N, Ryu S W, Choi K, et al. (2016) Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat Commun 7: 12277.
  • 48 Véron P, Segura E, Sugano G, et al. (2005) Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells. Blood Cells Mol Dis 35: 81-88.    
  • 49 Morishita M, Takahashi Y, Nishikawa M, et al. (2015) Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J Pharm Sci 104: 705-713.    
  • 50 Delcayre A, Estelles A, Sperinde J, et al. (2005) Exosome display technology: applications to the development of new diagnostics and therapeutics. Blood Cells Mol Dis 35: 158-168.    
  • 51 Stickney Z, Losacco J, McDevitt S, et al. (2016) Development of exosome surface display technology in living human cells. Biochem Biophys Res Commun 472: 53-59.    
  • 52 Akao Y, Iio A, Itoh T, et al. (2011) Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther 19: 395-399.    
  • 53 Ohno S, Takanashi M, Sudo K, et al. (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21: 185-191.    
  • 54 Munoz J L, Bliss S A, Greco S J, et al. (2013) Delivery of functional anti-mir-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids 2: e126.
  • 55 Alvarez-Erviti L, Seow Y, Yin H, et al. (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29: 341-345.    
  • 56 Cooper J M, Wiklander P, Nordin J Z, et al. (2014) Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov Disord 29: 1476-1485.    
  • 57 Bala S, Csak T, Momen-Heravi F, et al. (2015) Biodistribution and function of extracellular miRNA-155 in mice. Sci Rep 5: 10721.
  • 58 Momen-Heravi F, Bala S, Bukong T, et al. (2014) Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomed Nanotechnol Biol Med 10: 1517-1527.    
  • 59 Kim M S, Haney M J, Zhao Y, et al. (2016) Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomed Nanotechnol Biol Med 12: 655-664.    
  • 60 Martins-Marques T, Pinho M J, Zuzarte M, et al. (2016) Presence of CX43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin. J Extracell Vesicles 5: 1-12.
  • 61 Tian Y, Li S, Song J, et al. (2014) A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35: 2383-2390.    
  • 62 Nakase I, Noguchi K, Fujii I, et al. (2016) Vectorization of biomacromolecules into cells using extracellular vesicles with enhanced internalization induced by macropinocytosis. Sci Rep 6: 34937.
  • 63 Kooijmans S, Stremersch S, Braeckmans K, et al. (2013) Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release 172: 229-238.    
  • 64 Salama A, Fichou N, Allard M, et al. (2014) MicroRNA-29b modulates innate and antigen-specific immune responses in mouse models of autoimmunity. Plos One 9: e106153.
  • 65 Shtam T A, Kovalev R A, Varfolomeeva E, et al. (2013) Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal 11: 88.
  • 66 Fuhrmann G, Serio A, Mazo M, et al. (2015) Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J Control Release 205: 35-44.    
  • 67 Haney M J, Klyachko N L, Zhao Y, et al. (2015) Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release 207: 18-30.    
  • 68 Yang T, Martin P, Fogarty B, et al. (2015) Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in danio rerio. Pharm Res 32: 2003-2014.    
  • 69 Sun D, Zhuang X, Xiang X, et al. (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther.18: 1606-1614.
  • 70 Zhuang X, Xiang X, Grizzle W, et al. (2009) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19: 1769-1779.
  • 71 Yamanaka M, Nakamura S, Inoue A, et al. (2010) Induction of cell size vesicles from human lymphoma cell lines and their application to drug carriers. Cytotechnology 62: 287-291.    
  • 72 Saari H, Lázaro-Ibáñez E, Viitala T, et al. (2015) Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of paclitaxel in autologous prostate cancer cells. J Control Release 220: 727-37.    
  • 73 Hoshino A, Costa-Silva B, Shen T L, et al. (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527: 329-335.    
  • 74 Mulcahy L A., Pink R C, Carter D (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3: 24641.
  • 75 Tominaga N, Kosaka N, Ono M, et al. (2015) Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun 6: 6716.
  • 76 Smyth T, Petrova K, Payton N, et al. (2014) Surface functionalization of exosomes using click chemistry. Bioconjug Chem 25: 1777-1784.    
  • 77 Koppers-Lalic D, Hogenboom M M, Middeldorp J M, et al. (2013) Virus-modified exosomes for targeted RNA delivery; a new approach in nanomedicine. Adv Drug Deliv Rev 65: 348-356.    
  • 78 Sato Y T, Umezaki K, Sawada S, et al. (2016) Engineering hybrid exosomes by membrane fusion with liposomes. Sci Rep 6: 21933.
  • 79 Immordino L, Dosio F, Cattel L, et al. (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 1: 297-315.    
  • 80 Lai C P, Mardini O, Ericsson M, et al. (2014) Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8: 483-494.    
  • 81 Takahashi Y, Nishikawa M, Shinotsuka H, et al. (2013) Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol.165: 77-84.
  • 82 Imai T, Takahashi Y, Nishikawa M, et al. (2015) Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice. J Extracell Vesicles 4: 1-23
  • 83 Matsumoto A, Takahashi Y, Nishikawa M, et al. (2016) Role of phosphatidylserine-derived negative surface charges in the recognition and uptake of intravenously injected B16BL6-derived exosomes by macrophages. J Pharm Sci 1-8.
  • 84 Wiklander O, Nordin J Z, Loughlin A O, et al. (2015) Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4: 26316.
  • 85 Kooijmans S, Fliervoet L, Meel R, et al. (2016) PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release 224: 77-85.    

 

This article has been cited by

  • 1. Gyeonghui Yu, Heesun Jung, Yoon Young Kang, Hyejung Mok, Comparative evaluation of cell- and serum-derived exosomes to deliver immune stimulators to lymph nodes, Biomaterials, 2018, 10.1016/j.biomaterials.2018.02.003
  • 2. Masaharu Somiya, Yusuke Yoshioka, Takahiro Ochiya, Biocompatibility of highly purified bovine milk-derived extracellular vesicles, Journal of Extracellular Vesicles, 2018, 7, 1, 1440132, 10.1080/20013078.2018.1440132
  • 3. Adriely Goes, Gregor Fuhrmann, Biogenic and Biomimetic Carriers as Versatile Transporters To Treat Infections, ACS Infectious Diseases, 2018, 10.1021/acsinfecdis.8b00030

Reader Comments

your name: *   your email: *  

Copyright Info: 2017, Takahiro Ochiya, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved