Advertisement

Exosomes as Therapeutic Vehicles for Cancer

  • Whasun Lim
  • Han-Soo KimEmail author
Review Article
  • 109 Downloads

Abstract

Background:

Exosomes are membrane-enclosed extracellular vesicles implicated in cell–cell communication. Exosomes contain proteins, mRNAs, non-coding RNAs (miRNAs and lncRNAs) and lipids that are derived from producing cells. These nano-sized vesicles are present in biofluids including blood, urine, saliva, amniotic fluid, semen and conditioned media of cultured cells.

Methods:

This review summarizes current progress on the strategies of development of diagnostic biomarkers and drug loading onto exosomes for overcoming cancer progression.

Results:

A number of studies indicate that the exosome appears to be a key player in tissue repair and regeneration of in a number of animal disease models. In addition, alterations of the molecular profiles in exosomes are known to be correlated with the disease progression including cancer, suggesting their usefulness in disease diagnosis and prognosis. Studies utilizing engineered exosomes either by chemical or biological methods have demonstrated promising results in a number of animal models with cancer.

Conclusion:

Understanding the molecular and cellular properties of exosomes offer benefits for cancer diagnosis by liquid biopsy and for their application in therapeutic drug delivery systems. Studies have shown that genetic or molecular engineering of exosomes augmented their target specificity and anticancer activity with less toxicity. Thus, deeper understanding of exosome biology will facilitate their therapeutic potential as an innovative drug delivery system for cancer.

Keywords

Exosomes Drug delivery Cancer Extracellular vesicles Target specificity 

Notes

Acknowledgements

This research was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (No. HI17C0929) and from the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by Ministry of Science and ICT (MSIT) (No. 2017M3A9B4042583), Republic of Korea.

Author contributions

WL: manuscript writing, conception and design, HSK: manuscript writing and final approval of manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

Ethical approval and consent to participate is not applicable to this article as no data were generated or analyzed during the current study.

References

  1. 1.
    Seo JY, Lee B, Kang TW, Noh JH, Kim MJ, Ji YB, et al. Electrostatically interactive injectable hydrogels for drug delivery. Tissue Eng Regen Med. 2018;15:513–20.Google Scholar
  2. 2.
    Antimisiaris SG, Mourtas S, Marazioti A. Exosomes and exosome-inspired vesicles for targeted drug delivery. Pharmaceutics. 2018;10:E218.Google Scholar
  3. 3.
    Lee JY, Kim HS. Extracellular vesicles in neurodegenerative diseases: a double-edged sword. Tissue Eng Regen Med. 2017;14:667–78.Google Scholar
  4. 4.
    Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967;13:269–88.Google Scholar
  5. 5.
    Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, et al. Tumor shedding and coagulation. Science. 1981;212:923–4.Google Scholar
  6. 6.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183:1161–72.Google Scholar
  7. 7.
    Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux JF, et al. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J. 2004;380:161–71.Google Scholar
  8. 8.
    van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. 2001;121:337–49.Google Scholar
  9. 9.
    Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;31:642–8.Google Scholar
  10. 10.
    Kim HS, Choi DY, Yun SJ, Choi SM, Kang JW, Jung JW, et al. Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J Proteome Res. 2012;11:839–49.Google Scholar
  11. 11.
    Johnstone RM, Bianchini A, Teng K. Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood. 1989;74:1844–51.Google Scholar
  12. 12.
    Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005;17:879–87.Google Scholar
  13. 13.
    Vella LJ, Sharples RA, Lawson VA, Masters CL, Cappai R, Hill AF. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J Pathol. 2007;211:582–90.Google Scholar
  14. 14.
    Keller S, Rupp C, Stoeck A, Runz S, Fogel M, Lugert S, et al. CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int. 2007;72:1095–102.Google Scholar
  15. 15.
    Admyre C, Johansson SM, Qazi KR, Filén JJ, Lahesmaa R, Norman M, et al. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007;179:1969–78.Google Scholar
  16. 16.
    Ogawa Y, Kanai-Azuma M, Akimoto Y, Kawakami H, Yanoshita R. Exosome-like vesicles with dipeptidyl peptidase IV in human saliva. Biol Pharm Bull. 2008;31:1059–62.Google Scholar
  17. 17.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.Google Scholar
  18. 18.
    Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, et al. Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res. 2008;7:5157–66.Google Scholar
  19. 19.
    Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem. 1998;273:20121–7.Google Scholar
  20. 20.
    Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147:599–610.Google Scholar
  21. 21.
    Skotland T, Hessvik NP, Sandvig K, Llorente A. Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J Lipid Res. 2019;60:9–18.Google Scholar
  22. 22.
    Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.Google Scholar
  23. 23.
    Xu R, Greening DW, Zhu HJ, Takahashi N, Simpson RJ. Extracellular vesicle isolation and characterization: toward clinical application. J Clin Invest. 2016;126:1152–62.Google Scholar
  24. 24.
    Li P, Kaslan M, Lee SH, Yao J, Gao Z. Progress in exosome isolation techniques. Theranostics. 2017;7:789–804.Google Scholar
  25. 25.
    Konoshenko MY, Lekchnov EA, Vlassov AV, Laktionov PP. Isolation of extracellular vesicles: general methodologies and latest trends. Biomed Res Int. 2018;2018:8545347.Google Scholar
  26. 26.
    Mathivanan S, Simpson RJ. ExoCarta: a compendium of exosomal proteins and RNA. Proteomics. 2009;9:4997–5000.Google Scholar
  27. 27.
    Ståhl AL, Johansson K, Mossberg M, Kahn R, Karpman D. Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr Nephrol. 2019;34:11–30.Google Scholar
  28. 28.
    McGough IJ, Vincent JP. Exosomes in developmental signalling. Development. 2016;143:2482–93.Google Scholar
  29. 29.
    Ismail N, Wang Y, Dakhlallah D, Moldovan L, Agarwal K, Batte K, et al. Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood. 2013;121:984–95.Google Scholar
  30. 30.
    Chaput N, Flament C, Viaud S, Taieb J, Roux S, Spatz A, et al. Dendritic cell derived-exosomes: biology and clinical implementations. J Leukoc Biol. 2006;80:471–8.Google Scholar
  31. 31.
    Näslund TI, Gehrmann U, Qazi KR, Karlsson MC, Gabrielsson S. Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. J Immunol. 2013;190:2712–9.Google Scholar
  32. 32.
    Viaud S, Terme M, Flament C, Taieb J, André F, Novault S, et al. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One. 2009;4:e4942.Google Scholar
  33. 33.
    Cheng L, Wang Y, Huang L. Exosomes from M1-polarized macrophages potentiate the cancer vaccine by creating a pro-inflammatory microenvironment in the lymph node. Mol Ther. 2017;25:1665–75.Google Scholar
  34. 34.
    Rajagopal C, Harikumar KB. The origin and functions of exosomes in cancer. Front Oncol. 2018;8:66.Google Scholar
  35. 35.
    Palmirotta R, Lovero D, Cafforio P, Felici C, Mannavola F, Pellè E, et al. Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology. Ther Adv Med Oncol. 2018;10:1758835918794630.Google Scholar
  36. 36.
    Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–8.Google Scholar
  37. 37.
    Liao J, Liu R, Shi YJ, Yin LH, Pu YP. Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer. Int J Oncol. 2016;48:2567–79.Google Scholar
  38. 38.
    Zhang H, Deng T, Liu R, Bai M, Zhou L, Wang X, et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun. 2017;8:15016.Google Scholar
  39. 39.
    Maji S, Chaudhary P, Akopova I, Nguyen PM, Hare RJ, Gryczynski I, et al. Exosomal Annexin II promotes angiogenesis and breast cancer metastasis. Mol Cancer Res. 2017;15:93–105.Google Scholar
  40. 40.
    Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150.Google Scholar
  41. 41.
    Ren J, Ding L, Zhang D, Shi G, Xu Q, Shen S, et al. Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics. 2018;8:3932–48.Google Scholar
  42. 42.
    Zhang R, Xia Y, Wang Z, Zheng J, Chen Y, Li X, et al. Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. Biochem Biophys Res Commun. 2017;490:406–14.Google Scholar
  43. 43.
    Hu X, Feng Y, Zhang D, Zhao SD, Hu Z, Greshock J, et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014;26:344–57.Google Scholar
  44. 44.
    Pan C, Yao G, Liu B, Ma T, Xia Y, Wei K, et al. Long noncoding RNA FAL1 promotes cell proliferation, invasion and epithelial-mesenchymal transition through the PTEN/AKT signaling axis in non-small cell lung cancer. Cell Physiol Biochem. 2017;43:339–52.Google Scholar
  45. 45.
    Xue M, Chen W, Xiang A, Wang R, Chen H, Pan J, et al. Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 2017;16:143.Google Scholar
  46. 46.
    Li B, Mao R, Liu C, Zhang W, Tang Y, Guo Z. LncRNA FAL1 promotes cell proliferation and migration by acting as a CeRNA of miR-1236 in hepatocellular carcinoma cells. Life Sci. 2018;197:122–9.Google Scholar
  47. 47.
    Esposito A, Criscitiello C, Locatelli M, Milano M, Curigliano G. Liquid biopsies for solid tumors: understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies. Pharmacol Ther. 2016;157:120–4.Google Scholar
  48. 48.
    Perakis S, Speicher MR. Emerging concepts in liquid biopsies. BMC Med. 2017;15:75.Google Scholar
  49. 49.
    Zhang S, Du L, Wang L, Jiang X, Zhan Y, Li J, et al. Evaluation of serum exosomal LncRNA-based biomarker panel for diagnosis and recurrence prediction of bladder cancer. J Cell Mol Med. 2019;23:1396–405.Google Scholar
  50. 50.
    Wang J, Yang K, Yuan W, Gao Z. Determination of serum exosomal H19 as a noninvasive biomarker for bladder cancer diagnosis and prognosis. Med Sci Monit. 2018;24:9307–16.Google Scholar
  51. 51.
    Rodríguez-Martínez A, de Miguel-Pérez D, Ortega FG, García-Puche JL, Robles-Fernández I, Exposito J, et al. Exosomal miRNA profile as complementary tool in the diagnostic and prediction of treatment response in localized breast cancer under neoadjuvant chemotherapy. Breast Cancer Res. 2019;21:21.Google Scholar
  52. 52.
    Stevic I, Müller V, Weber K, Fasching PA, Karn T, Marmé F, et al. Specific microRNA signatures in exosomes of triple-negative and HER2-positive breast cancer patients undergoing neoadjuvant therapy within the GeparSixto trial. BMC Med. 2018;16:179.Google Scholar
  53. 53.
    Zhai LY, Li MX, Pan WL, Chen Y, Li MM, Pang JX, et al. In situ detection of plasma exosomal MicroRNA-1246 for breast cancer diagnostics by a Au nanoflare probe. ACS Appl Mater Interfaces. 2018;10:39478–86.Google Scholar
  54. 54.
    Yang YN, Zhang R, Du JW, Yuan HH, Li YJ, Wei XL, et al. Predictive role of UCA1-containing exosomes in cetuximab-resistant colorectal cancer. Cancer Cell Int. 2018;18:164.Google Scholar
  55. 55.
    Lin Y, Dong H, Deng W, Lin W, Li K, Xiong X, et al. Evaluation of salivary exosomal chimeric GOLM1-NAA35 RNA as a potential biomarker in esophageal carcinoma. Clin Cancer Res. 2019.  https://doi.org/10.1158/078-0432.CCR-18-3169.
  56. 56.
    Lin XJ, Fang JH, Yang XJ, Zhang C, Yuan Y, Zheng L, et al. Hepatocellular carcinoma cell-secreted exosomal MicroRNA-210 promotes angiogenesis in vitro and in vivo. Mol Ther Nucleic Acids. 2018;11:243–52.Google Scholar
  57. 57.
    Sánchez CA, Andahur EI, Valenzuela R, Castellón EA, Fullá JA, Ramos CG, et al. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget. 2016;7:3993–4008.Google Scholar
  58. 58.
    Niu L, Song X, Wang N, Xue L, Song X, Xie L. Tumor-derived exosomal proteins as diagnostic biomarkers in non-small cell lung cancer. Cancer Sci. 2019;110:433–42.Google Scholar
  59. 59.
    Feng M, Zhao J, Wang L, Liu J. Upregulated expression of serum exosomal microRNAs as diagnostic biomarkers of lung adenocarcinoma. Ann Clin Lab Sci. 2018;48:712–8.Google Scholar
  60. 60.
    Yoshimura A, Sawada K, Nakamura K, Kinose Y, Nakatsuka E, Kobayashi M, et al. Exosomal miR-99a-5p is elevated in sera of ovarian cancer patients and promotes cancer cell invasion by increasing fibronectin and vitronectin expression in neighboring peritoneal mesothelial cells. BMC Cancer. 2018;18:1065.Google Scholar
  61. 61.
    Kitagawa T, Taniuchi K, Tsuboi M, Sakaguchi M, Kohsaki T, Okabayashi T, et al. Circulating pancreatic cancer exosomal RNAs for detection of pancreatic cancer. Mol Oncol. 2019;13:212–27.Google Scholar
  62. 62.
    Bjørnetrø T, Redalen KR, Meltzer S, Thusyanthan NS, Samiappan R, Jegerschöld C, et al. An experimental strategy unveiling exosomal microRNAs 486-5p, 181a-5p and 30d-5p from hypoxic tumour cells as circulating indicators of high-risk rectal cancer. J Extracell Vesicles. 2019;8:1567219.Google Scholar
  63. 63.
    Tesauro D, Accardo A, Diaferia C, Milano V, Guillon J, Ronga L, et al. Peptide-based drug-delivery systems in biotechnological applications: recent advances and perspectives. Molecules. 2019;24:E351.Google Scholar
  64. 64.
    Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2002;54:3–12.Google Scholar
  65. 65.
    Malam Y, Loizidou M, Seifalian AM. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol Sci. 2009;30:592–9.Google Scholar
  66. 66.
    Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2:347–60.Google Scholar
  67. 67.
    Gang J, Park SB, Hyung W, Choi EH, Wen J, Kim HS, et al. Magnetic poly epsilon-caprolactone nanoparticles containing Fe3O4 and gemcitabine enhance anti-tumor effect in pancreatic cancer xenograft mouse model. J Drug Target. 2007;15:445–53.Google Scholar
  68. 68.
    Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33:2373–87.Google Scholar
  69. 69.
    Basso J, Miranda A, Nunes S, Cova T, Sousa J, Vitorino C, et al. Hydrogel-based drug delivery nanosystems for the treatment of brain tumors. Gels. 2018;4:E62.Google Scholar
  70. 70.
    Suk JS, Xu Q, Kim N, Hanes J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99:28–51.Google Scholar
  71. 71.
    Kraft JC, Freeling JP, Wang Z, Ho RJ. Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci. 2014;103:29–52.Google Scholar
  72. 72.
    Ramalingam P, Ko YT. Enhanced oral delivery of curcumin from N-trimethyl chitosan surface-modified solid lipid nanoparticles: pharmacokinetic and brain distribution evaluations. Pharm Res. 2015;32:389–402.Google Scholar
  73. 73.
    Dams ET, Laverman P, Oyen WJ, Storm G, Scherphof GL, van Der Meer JW, et al. Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. 2000;292:1071–9.Google Scholar
  74. 74.
    Ishida T, Kashima S, Kiwada H. The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release. 2008;126:162–5.Google Scholar
  75. 75.
    Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles—endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta. 2014;1846:75–87.Google Scholar
  76. 76.
    Wiklander OP, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I, et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015;4:26316.Google Scholar
  77. 77.
    Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32:2003–14.Google Scholar
  78. 78.
    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.Google Scholar
  79. 79.
    Kooijmans SAA, Schiffelers RM, Zarovni N, Vago R. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: new nanotools for cancer treatment. Pharmacol Res. 2016;111:487–500.Google Scholar
  80. 80.
    Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12:655–64.Google Scholar
  81. 81.
    Munagala R, Aqil F, Jeyabalan J, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371:48–61.Google Scholar
  82. 82.
    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.Google Scholar
  83. 83.
    Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 2010;38:7248–59.Google Scholar
  84. 84.
    Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21:R125–34.Google Scholar
  85. 85.
    Wahlgren J, De L Karlson T, Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 2012;40:e130.Google Scholar
  86. 86.
    Pan Q, Ramakrishnaiah V, Henry S, Fouraschen S, de Ruiter PE, Kwekkeboom J, et al. Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). Gut. 2012;61:1330–9.Google Scholar
  87. 87.
    Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21:185–91.Google Scholar
  88. 88.
    Greco KA, Franzen CA, Foreman KE, Flanigan RC, Kuo PC, Gupta GN. PLK-1 silencing in bladder cancer by siRNA delivered with exosomes. Urology. 2016;91:241.e1–7.Google Scholar
  89. 89.
    Hood JL, Scott MJ, Wickline SA. Maximizing exosome colloidal stability following electroporation. Anal Biochem. 2014;448:41–9.Google Scholar
  90. 90.
    Kooijmans SAA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJA, et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172:229–38.Google Scholar
  91. 91.
    Shtam TA, Kovalev RA, Varfolomeeva EY, Makarov EM, Kil YV, Filatov MV. Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal. 2013;11:88.Google Scholar
  92. 92.
    Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, et al. Exosome-mediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing. Mol Ther. 2016;24:1836–47.Google Scholar
  93. 93.
    Luan X, Sansanaphongpricha K, Myers I, Chen H, Yuan H, Sun D. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol Sin. 2017;38:754–63.Google Scholar
  94. 94.
    Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30.Google Scholar
  95. 95.
    Pascucci L, Coccè V, Bonomi A, Ami D, Ceccarelli P, Ciusani E, et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release. 2014;192:262–70.Google Scholar
  96. 96.
    Lee J, Kim J, Jeong M, Lee H, Goh U, Kim H, et al. Liposome-based engineering of cells to package hydrophobic compounds in membrane vesicles for tumor penetration. Nano Lett. 2015;15:2938–44.Google Scholar
  97. 97.
    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.Google Scholar
  98. 98.
    Kalimuthu S, Gangadaran P, Rajendran RL, Zhu L, Oh JM, Lee HW, et al. A new approach for loading anticancer drugs into mesenchymal stem cell-derived exosome mimetics for cancer therapy. Front Pharmacol. 2018;9:1116.Google Scholar
  99. 99.
    Kim M, Yun HW, Park DY, Choi BH, Min BH. Three-dimensional spheroid culture increases exosome secretion from mesenchymal stem cells. Tissue Eng Regen Med. 2018;15:427–36.Google Scholar
  100. 100.
    Gudbergsson JM, Johnsen KB, Skov MN, Duroux M. Systematic review of factors influencing extracellular vesicle yield from cell cultures. Cytotechnology. 2016;68:579–92.Google Scholar
  101. 101.
    King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.Google Scholar
  102. 102.
    Kojima R, Bojar D, Rizzi G, Hamri GC, El-Baba MD, Saxena P, et al. Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat Commun. 2018;9:1305.Google Scholar
  103. 103.
    Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335:201–4.Google Scholar
  104. 104.
    Lou G, Song X, Yang F, Wu S, Wang J, Chen Z, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015;8:122.Google Scholar
  105. 105.
    Wang X, Zhang H, Bai M, Ning T, Ge S, Deng T, et al. Exosomes serve as nanoparticles to deliver anti-miR-214 to reverse chemoresistance to cisplatin in gastric cancer. Mol Ther. 2018;26:774–83.Google Scholar
  106. 106.
    Li H, Yang C, Shi Y, Zhao L. Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress Sorafenib resistance in hepatocellular carcinoma. J Nanobiotechnology. 2018;16:103.Google Scholar
  107. 107.
    Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.Google Scholar
  108. 108.
    Statello L, Maugeri M, Garre E, Nawaz M, Wahlgren J, Papadimitriou A, et al. Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes. PLoS One. 2018;13:e0195969.Google Scholar
  109. 109.
    Fu H, Yang H, Zhang X, Wang B, Mao J, Li X, et al. Exosomal TRIM3 is a novel marker and therapy target for gastric cancer. J Exp Clin Cancer Res. 2018;37:162.Google Scholar
  110. 110.
    Rivoltini L, Chiodoni C, Squarcina P, Tortoreto M, Villa A, Vergani B, et al. TNF-related apoptosis-inducing ligand (TRAIL)-armed exosomes deliver proapoptotic signals to tumor site. Clin Cancer Res. 2016;22:3499–512.Google Scholar
  111. 111.
    Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21:101–8.Google Scholar
  112. 112.
    Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35:2383–90.Google Scholar
  113. 113.
    Grapp M, Wrede A, Schweizer M, Hüwel S, Galla HJ, Snaidero N, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nat Commun. 2013;4:2123.Google Scholar

Copyright information

© The Korean Tissue Engineering and Regenerative Medicine Society 2019

Authors and Affiliations

  1. 1.Department of Biomedical Science, College of Medical ConvergenceCatholic Kwandong UniversityGangneung-siRepublic of Korea
  2. 2.Basic Research Division, Biomedical Institute of Mycological Resource, College of MedicineCatholic Kwandong UniversityGangneung-siRepublic of Korea
  3. 3.Department of Food and Nutrition, College of Science and TechnologyKookmin UniversitySeoulRepublic of Korea

Personalised recommendations