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Imaging and Therapeutic Potential of Extracellular Vesicles

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Design and Applications of Nanoparticles in Biomedical Imaging

Abstract

Extracellular vesicles (EVs) are multifaceted subcellular entities that act as a far-reaching intercellular communication pathway controlling cell signaling. Such unique properties stem from the extraordinary ability of EVs to transfer biomolecules between neighbor and distal cells. The possibility of engineering EVs for imaging or therapeutic purposes is now an active research field. On the one side, EV engineering with an image tracer aims to enable biodistribution investigation, which is fundamental for deciphering the complex fate of EV in the organism. On the other side, vesicle engineering with drug or heating nanoparticles attempts to translate such cell communication effectors into an intrinsically biocompatible bio-inspired vector for therapy. Herein we provide an overview of critical steps in EV engineering such as production, loading, isolation, and characterization. We also focus on recent studies evidencing that EVs may be tracked by imaging approaches or harnessed for the delivery of therapeutic agents via the introduction of exogenous cargoes such as nanoparticles, fluorescent dyes, nucleic acids, or drugs. Future investigations may bring along ultimate proofs to ensure the safety and efficacy of EVs loaded with exogenous cargoes including reproducible and scalable production, loading and isolation techniques, rigorous characterization, as well as thorough pharmacokinetic and toxicological studies. The advances in perspectives are expected to overcome current challenges in the field and move engineered EVs to the clinical practice.

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References

  1. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak M. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487–95.

    Article  CAS  PubMed  Google Scholar 

  2. Hugel B, Martínez MC, Kunzelmann C, Freyssinet J-M. Membrane microparticles: two sides of the coin. Physiology. 2005;20(1):22–7.

    Article  CAS  PubMed  Google Scholar 

  3. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010;78(9):838–48.

    Article  CAS  PubMed  Google Scholar 

  4. Mause SF, Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res. 2010;107(9):1047–57.

    Article  CAS  PubMed  Google Scholar 

  5. Jimenez JJ, Jy W, Mauro LM, Soderland C, Horstman LL, Ahn YS. Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis. Thromb Res. 2003;109(4):175–80.

    Article  CAS  PubMed  Google Scholar 

  6. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159(3):499–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Camacho L, Guerrero P, Marchetti D. MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes. PLoS One. 2013;8(9):e73790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967;13(3):269–88.

    Article  CAS  PubMed  Google Scholar 

  9. Krause M, Samoylenko A, Vainio SJ. Exosomes as renal inductive signals in health and disease, and their application as diagnostic markers and therapeutic agents. Front Cell Dev Biol. 2015;3:65.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Owens AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res. 2011;108(10):1284–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cloutier N, Tan S, Boudreau LH, Cramb C, Subbaiah R, Lahey L, Albert A, Shnayder R, Gobezie R, Nigrovic PA. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med. 2013;5(2):235–49.

    Article  CAS  PubMed  Google Scholar 

  12. Holder BS, Tower CL, Jones CJ, Aplin JD, Abrahams VM. Heightened pro-inflammatory effect of preeclamptic placental microvesicles on peripheral blood immune cells in humans. Biol Reprod. 2012;86(4):103.

    Article  PubMed  CAS  Google Scholar 

  13. Prakash PS, Caldwell CC, Lentsch AB, Pritts TA, Robinson BR. Human microparticles generated during sepsis in patients with critical illness are neutrophil-derived and modulate the immune response. J Trauma Acute Care Surg. 2012;73(2):401–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619–24.

    Article  CAS  PubMed  Google Scholar 

  15. Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res. 2007;67(7):2912–5.

    Article  CAS  PubMed  Google Scholar 

  16. Kharaziha P, Ceder S, Li Q, Panaretakis T. Tumor cell-derived exosomes: a message in a bottle. Biochim Biophys Acta. 2012;1826(1):103–11.

    CAS  PubMed  Google Scholar 

  17. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412–20.

    CAS  PubMed  Google Scholar 

  18. Pan B-T, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33(3):967–78.

    Article  CAS  PubMed  Google Scholar 

  19. Lee Y, El Andaloussi S, Wood MJA. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21(R1):R125–34.

    Article  CAS  PubMed  Google Scholar 

  20. Akers J, Gonda D, Kim R, Carter B, Chen C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113(1):1–11.

    Article  PubMed  Google Scholar 

  21. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–79.

    CAS  PubMed  Google Scholar 

  22. Leventis PA, Grinstein S. The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys. 2010;39:407–27.

    Article  CAS  PubMed  Google Scholar 

  23. Arraud N, Linares R, Tan S, Gounou C, Pasquet JM, Mornet S, Brisson AR. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014;12(5):614–27.

    Article  CAS  PubMed  Google Scholar 

  24. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676–705.

    Article  PubMed  CAS  Google Scholar 

  26. Utleg AG, Yi EC, Xie T, Shannon P, White JT, Goodlett DR, Hood L, Lin B. Proteomic analysis of human prostasomes. Prostate. 2003;56(2):150–61.

    Article  CAS  PubMed  Google Scholar 

  27. Caby M-P, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005;17(7):879–87.

    Article  CAS  PubMed  Google Scholar 

  28. Pisitkun T, Shen R-F, Knepper MA. Identification and proteomic profiling of exosomes in human urine. PNAS. 2004;101(36):13368–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ogawa Y, Miura Y, Harazono A, Kanai-Azuma M, Akimoto Y, Kawakami H, Yamaguchi T, Toda T, Endo T, Tsubuki M. Proteomic analysis of two types of exosomes in human whole saliva. Biol Pharm Bull. 2011;34(1):13–23.

    Article  CAS  PubMed  Google Scholar 

  30. Admyre C, Johansson SM, Qazi KR, Filén J-J, Lahesmaa R, Norman M, Neve EPA, Scheynius A, Gabrielsson S. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007;179(3):1969–78.

    Article  CAS  PubMed  Google Scholar 

  31. Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS. Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol. 2008;79(1):12–7.

    Article  CAS  PubMed  Google Scholar 

  32. Andre F, Schartz NEC, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002;360(9329):295–305.

    Article  CAS  PubMed  Google Scholar 

  33. Masyuk AI, Huang BQ, Ward CJ, Gradilone SA, Banales JM, Masyuk TV, Radtke B, Splinter PL, LaRusso NF. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol. 2010;299(4):G990–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tanimura A, McGregor DH, Anderson HC. Matrix vesicles in atherosclerotic calcification. Exp Biol Med. 1983;172(2):173–7.

    Article  CAS  Google Scholar 

  35. Fischer von Mollard G, Mignery GA, Baumert M, Perin MS, Hanson TJ, Burger PM, Jahn R, Südhof TC. rab3 is a small GTP-binding protein exclusively localized to synaptic vesicles. PNAS. 1990;87(5):1988–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Le Pecq J-B. Dexosomes as a therapeutic cancer vaccine: from bench to bedside. Blood Cells Mol Dis. 2005;35(2):129–35.

    Article  PubMed  CAS  Google Scholar 

  37. Chaput N, Schartz N, Andre F, Zitvogel L. Exosomes for immunotherapy of cancer. New trends in cancer for the 21st century. New York: Springer; 2003. p. 215–21.

    Google Scholar 

  38. Shen Y, Torchia MLG, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe. 2012;12(4):509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yeo RWY, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65(3):336–41.

    Article  CAS  PubMed  Google Scholar 

  40. Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011;6(4):481–92.

    Article  PubMed  Google Scholar 

  41. Riches A, Campbell E, Borger E, Powis S. Regulation of exosome release from mammary epithelial and breast cancer cells—a new regulatory pathway. Eur J Cancer. 2014;50(5):1025–34.

    Article  CAS  PubMed  Google Scholar 

  42. Sun L, Wang H-X, Zhu X-J, Wu P-H, Chen W-Q, Zou P, Li Q-B, Chen Z-C. Serum deprivation elevates the levels of microvesicles with different size distributions and selectively enriched proteins in human myeloma cells in vitro. Acta Pharmacol Sin. 2014;35(3):381–93.

    Article  CAS  PubMed  Google Scholar 

  43. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12(1):421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Headland SE, Jones HR, D'Sa AS, Perretti M, Norling LV. Cutting-edge analysis of extracellular microparticles using imagestreamx imaging flow cytometry. Sci Rep. 2014;4:5237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pick H, Schmid EL, Tairi A-P, Ilegems E, Hovius R, Vogel H. Investigating Cellular Signaling Reactions in Single Attoliter Vesicles J Am Chem Soc. 2005;127(9):2908–12.

    CAS  PubMed  Google Scholar 

  46. Mao Z, Cartier R, Hohl A, Farinacci M, Dorhoi A, Nguyen T-L, Mulvaney P, Ralston J, Kaufmann SHE, Möhwald H, Wang D. Cells as Factories for Humanized Encapsulation Nano Lett. 2011;11(5):2152–6.

    CAS  PubMed  Google Scholar 

  47. Momen-Heravi F, Bala S, Kodys K, Szabo G. Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS. Sci Rep. 2015:5.

    Google Scholar 

  48. Machluf M, Bronshtein T. Liposomal compositions and uses of same patent. 2010;US20120164214 A1.

    Google Scholar 

  49. Toledano Furman NE, Lupu-Haber Y, Bronshtein T, Kaneti L, Letko N, Weinstein E, Baruch L, Machluf M. Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett. 2013;13(7):3248–55.

    Article  CAS  PubMed  Google Scholar 

  50. Jo W, Jeong D, Kim J, Cho S, Jang SC, Han C, Kang JY, Gho YS, Park J. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. Lab Chip. 2014;14(7):1261–9.

    Article  CAS  PubMed  Google Scholar 

  51. Jang SC, Kim OY, Yoon CM, Choi D-S, Roh T-Y, Park J, Nilsson J, Lötvall J, Kim Y-K, Gho YS. Bioinspired Exosome-Mimetic Nanovesicles for Targeted Delivery of Chemotherapeutics to Malignant Tumors ACS Nano. 2013;7(9):7698–710.

    CAS  PubMed  Google Scholar 

  52. Jo W, Kim J, Yoon J, Jeong D, Cho S, Jeong H, Yoon Y, Kim S, Gho Y, Park J. Large-scale generation of cell-derived nanovesicles. Nanoscale. 2014;6(20):12056–64.

    Article  CAS  PubMed  Google Scholar 

  53. Yoon J, Jo W, Jeong D, Kim J, Jeong H, Park J. Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. Biomaterials. 2015;59:12–20.

    Article  CAS  PubMed  Google Scholar 

  54. Yun S-S, Yoon SY, Song M-K, Im S-H, Kim S, Lee J-H, Yang S. Handheld mechanical cell lysis chip with ultra-sharp silicon nano-blade arrays for rapid intracellular protein extraction. Lab Chip. 2010;10(11):1442–6.

    Article  CAS  PubMed  Google Scholar 

  55. Silva AKA, Di Corato R, Pellegrino T, Chat S, Pugliese G, Luciani N, Gazeau F, Wilhelm C. Cell-derived vesicles as a bioplatform for the encapsulation of theranostic nanomaterials. Nanoscale. 2013;5(23):11374–84.

    Article  PubMed  CAS  Google Scholar 

  56. Silva AK, Luciani N, Gazeau F, Aubertin K, Bonneau S, Chauvierre C, Letourneur D, Wilhelm C. Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Nanomed Nanotech Biol Med. 2015;11(3):645–55.

    Article  CAS  Google Scholar 

  57. Silva AK, Kolosnjaj-Tabi J, Bonneau S, Marangon I, Boggetto N, Aubertin K, Clément O, Bureau MF, Luciani N, Gazeau F. Magnetic and photoresponsive theranosomes: translating cell-released vesicles into smart nanovectors for cancer therapy. ACS Nano. 2013;7(6):4954–66.

    Article  CAS  PubMed  Google Scholar 

  58. Mao Z, Cartier R, Hohl A, Farinacci M, Dorhoi A, Nguyen T-L, Mulvaney P, Ralston J, Kaufmann SH, Möhwald H. Cells as factories for humanized encapsulation. Nano Lett. 2011;11(5):2152–6.

    Article  CAS  PubMed  Google Scholar 

  59. Wiklander OPB, Nordin JZ, O’Loughlin A, Gustafsson Y, Corso G, Mäger I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CIE, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJA, Andaloussi SEL. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015:4. 10.3402/jev.v4.26316.

  60. Wahlgren J, Karlson TDL, Brisslert M, Vaziri Sani F, Telemo E, Sunnerhagen P, Valadi H. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes Nucleic Acids Res. 2012:1–12.

    Google Scholar 

  61. Ohno S-I, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21(1):185–91.

    Article  CAS  PubMed  Google Scholar 

  62. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, Strobel T, Breakefield XO, Saydam O. Genetically Engineered Microvesicles Carrying Suicide mRNA/Protein Inhibit Schwannoma Tumor Growth Mol Ther. 2013;21(1):101–8.

    CAS  PubMed  Google Scholar 

  63. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. van Balkom BW, Eisele AS, Pegtel DM, Bervoets S, Verhaar MC. Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J Extracell Vesicles. 2015;4:26760.

    PubMed  Google Scholar 

  65. Kanada M, Bachmann MH, Hardy JW, Frimannson DO, Bronsart L, Wang A, Sylvester MD, Schmidt TL, Kaspar RL, Butte MJ. Differential fates of biomolecules delivered to target cells via extracellular vesicles. PNAS. 2015;112(12):E1433–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 Biotech. 2011;29(4):341–5.

    Article  CAS  Google Scholar 

  67. Shen B, Wu N, Yang J-M, Gould SJ. Protein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors J Biol Chem. 2011;286(16):14383–95.

    CAS  PubMed  Google Scholar 

  68. Vats N, Wilhelm C, Rautou P-E, Poirier-Quinot M, Péchoux C, Devue C, Boulanger CM, Gazeau F. Magnetic tagging of cell-derived microparticles: new prospects for imaging and manipulation of these mediators of biological information. Nanomedicine. 2010;5(5):727–38.

    Article  CAS  PubMed  Google Scholar 

  69. Rank A, Nieuwland R, Crispin A, Grützner S, Iberer M, Toth B, Pihusch R. Clearance of platelet microparticles in vivo. Platelets. 2011;22(2):111–6.

    Article  CAS  PubMed  Google Scholar 

  70. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, Miller D, Zhang H-G. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19(10):1769–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang H-G. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18(6):883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, Yin V, Lockman P, Bai S. Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio Pharm Res. 2015;32(6):2003–14.

    CAS  PubMed  Google Scholar 

  74. Willekens FL, Werre JM, Kruijt JK, Roerdinkholder-Stoelwinder B, Groenen-Döpp YA, van den Bos AG, Bosman GJ, van Berkel TJ. Liver Kupffer cells rapidly remove red blood cell–derived vesicles from the circulation by scavenger receptors. Blood. 2005;105(5):2141–5.

    Article  CAS  PubMed  Google Scholar 

  75. Aaseth J, Alexander J, Norseth T. Uptake of 51CrChromate by human erythrocytes–a role of glutathione. Acta Pharmacol Toxicol. 1982;50(4):310–5.

    Article  CAS  Google Scholar 

  76. Kooijmans SA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJ, Schiffelers RM, Raemdonck K, Vader P. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172(1):229–38.

    Article  CAS  PubMed  Google Scholar 

  77. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, Batrakova EV. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. György B, Módos K, Pállinger É, Pálóczi K, Pásztói M, Misják P, Deli MA, Sipos Á, Szalai A, Voszka I, Polgár A, Tóth K, Csete M, Nagy G, Gay S, Falus A, Kittel Á, Buzás EI. Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood. 2011;117(4):e39–48.

    Article  PubMed  CAS  Google Scholar 

  79. Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006:3.22.1–3.9.

    Google Scholar 

  80. Lamparski HG, Metha-Damani A, Yao J-Y, Patel S, Hsu D-H, Ruegg C, Le Pecq J-B. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods. 2002;270(2):211–26.

    Article  CAS  PubMed  Google Scholar 

  81. Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics. 2010;9(2):197–208.

    Article  CAS  PubMed  Google Scholar 

  82. Tauro BJ, Greening DW, Mathias RA, Mathivanan S, Ji H, Simpson RJ. Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Mol Cell Proteomics. 2013;12(3):587–98.

    Article  CAS  PubMed  Google Scholar 

  83. Tauro BJ, Greening DW, Mathias RA, Ji H, Mathivanan S, Scott AM, Simpson RJ. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012;56(2):293–304.

    Article  CAS  PubMed  Google Scholar 

  84. Chen C, Skog J, Hsu C-H, Lessard RT, Balaj L, Wurdinger T, Carter BS, Breakefield XO, Toner M, Irimia D. Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip. 2010;10(4):505–11.

    Article  CAS  PubMed  Google Scholar 

  85. Lee K, Shao H, Weissleder R, Lee H. Acoustic Purification of Extracellular Microvesicles ACS Nano. 2015;9(3):2321–7.

    CAS  PubMed  Google Scholar 

  86. Böing AN, van der Pol E, Grootemaat AE, Coumans FAW, Sturk A, Nieuwland R. Single-step isolation of extracellular vesicles by size-exclusion chromatography J Extracell Vesicles. 2014:3. 10.3402/jev.v3.23430.

  87. Welton JL, Webber JP, Botos L-A, Jones M, Clayton A. Ready-made chromatography columns for extracellular vesicle isolation from plasma. J Extracell Vesicles. 2015;4.

    Google Scholar 

  88. Filipe V, Hawe A, Jiskoot W. Critical Evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the Measurement of Nanoparticles and Protein Aggregates Pharm Res. 2010;27(5):796–810.

    CAS  PubMed  Google Scholar 

  89. Pol E, Coumans F, Varga Z, Krumrey M, Nieuwland R. Innovation in detection of microparticles and exosomes. J Thromb Haemost. 2013;11(s1):36–45.

    PubMed  Google Scholar 

  90. Hoo C, Starostin N, West P, Mecartney M. A comparison of atomic force microscopy (AFM) and dynamic light scattering (DLS) methods to characterize nanoparticle size distributions. J Nanopart Res. 2008;10(1):89–96.

    Article  CAS  Google Scholar 

  91. Momen-Heravi F, Balaj L, Alian S, Tigges J, Toxavidis V, Ericsson M, Distel RJ, Ivanov AR, Skog J, Kuo WP. Alternative methods for characterization of extracellular vesicles. Front Physiol. 2012;3:354.

    PubMed  PubMed Central  Google Scholar 

  92. Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJP, Hole P, Carr B, Redman CWG, Harris AL, Dobson PJ, Harrison P, Sargent IL. Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomed Nanotech Biol Med. 2011;7(6):780–8.

    Article  CAS  Google Scholar 

  93. van der Pol E, Coumans FAW, Grootemaat AE, Gardiner C, Sargent IL, Harrison P, Sturk A, van Leeuwen TG, Nieuwland R. Particle size distribution of exosomes and microvesicles determined by transmission electron microscopy, flow cytometry, nanoparticle tracking analysis, and resistive pulse sensing. J Thromb Haemost. 2014;12(7):1182–92.

    Article  PubMed  Google Scholar 

  94. Yuana Y, Oosterkamp T, Bahatyrova S, Ashcroft B, Garcia Rodriguez P, Bertina R, Osanto S. Atomic force microscopy: a novel approach to the detection of nanosized blood microparticles. J Thromb Haemost. 2010;8(2):315–23.

    Article  CAS  PubMed  Google Scholar 

  95. Kanno T, Yamada T, Iwabuki H, Tanaka H, Kuroda SI, Tanizawa K, Kawai T. Size distribution measurement of vesicles by atomic force microscopy. Anal Biochem. 2002;309(2):196–9.

    Article  CAS  PubMed  Google Scholar 

  96. Van Der Pol E, Hoekstra AG, Sturk A, Otto C, Van Leeuwen TG, Nieuwland R. Optical and non-optical methods for detection and characterization of microparticles and exosomes. J Thromb Haemost. 2010;8(12):2596–607.

    Article  PubMed  Google Scholar 

  97. Andriola Silva AK, Di Corato R, Gazeau F, Pellegrino T, Wilhelm C. Magnetophoresis at the nanoscale: tracking the magnetic targeting efficiency of nanovectors. Nanomedicine. 2012;7(11):1713–27.

    Article  CAS  PubMed  Google Scholar 

  98. Lacroix R, Robert S, Poncelet P, Kasthuri RS, Key NS, Dignat-George F. Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost. 2010;8(11):2571–4.

    Article  CAS  PubMed  Google Scholar 

  99. Arraud N, Gounou C, Linares R, Brisson AR. A simple flow cytometry method improves the detection of phosphatidylserine-exposing extracellular vesicles. J Thromb Haemost. 2015;13(2):237–47.

    Article  CAS  PubMed  Google Scholar 

  100. Palomo L, Casal E, Royo F, Cabrera D, van-Liempd S, Falcon-Perez JM. Considerations for applying metabolomics to the analysis of extracellular vesicles. Front Immunol. 2014;5:651.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kreimer S, Belov AM, Ghiran I, Murthy SK, Frank DA, Ivanov AR. Mass spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics. J Proteome Res. 2015;14:2367–84.

    Article  CAS  PubMed  Google Scholar 

  102. Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014;3:10.3402.

    Google Scholar 

  103. Webber J, Clayton A. How pure are your vesicles? J Extracell Vesicles. 2013;2:10.3402

    Google Scholar 

  104. Al Faraj A, Gazeau F, Wilhelm C, Devue C, Guérin CL, Péchoux C, Paradis V, Clément O, Boulanger CM, Rautou P-E. Endothelial cell-derived microparticles loaded with iron oxide nanoparticles: feasibility of MR imaging monitoring in mice. Radiology. 2012;263(1):169–78.

    Article  PubMed  Google Scholar 

  105. Grange C, Tapparo M, Bruno S, Chatterjee D, Quesenberry PJ, Tetta C, Camussi G. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int J Mol Med. 2014;33(5):1055–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire CA, Chen JW, Tannous BA, Breakefield XO. Dynamic Biodistribution of Extracellular Vesicles in Vivo Using a Multimodal Imaging Reporter ACS Nano. 2014;8(1):483–94.

    CAS  PubMed  Google Scholar 

  107. Barenholz YC. Doxil®—the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160(2):117–34.

    Article  CAS  PubMed  Google Scholar 

  108. Wang R, Billone PS, Mullett WM. Nanomedicine in action: an overview of cancer nanomedicine on the market and in clinical trials. J Nanomater. 2013;2013:1.

    Google Scholar 

  109. Yoo J-W, Irvine DJ, Discher DE, Mitragotri S. Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat Rev Drug Discov. 2011;10(7):521–35.

    Article  CAS  PubMed  Google Scholar 

  110. 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(1):75–87.

    CAS  PubMed  Google Scholar 

  111. Natasha G, Gundogan B, Tan A, Farhatnia Y, Wu W, Rajadas J, Seifalian AM. Exosomes as Immunotheranostic Nanoparticles Clin Ther. 2014;36(6):820–9.

    CAS  PubMed  Google Scholar 

  112. Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release. 2015;219:396–405.

    Article  CAS  PubMed  Google Scholar 

  113. Yin W, Ouyang S, Li Y, Xiao B, Yang H. Immature Dendritic Cell-Derived Exosomes: a Promise Subcellular Vaccine for Autoimmunity Inflammation. 2013;36(1):232–40.

    CAS  PubMed  Google Scholar 

  114. Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, Wei J, Nie G. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–90.

    Article  CAS  PubMed  Google Scholar 

  115. Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335(1):201–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Claire Wilhelm or Amanda K. A. Silva .

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Piffoux, M., Gazeau, F., Wilhelm, C., Silva, A.K.A. (2017). Imaging and Therapeutic Potential of Extracellular Vesicles. In: Bulte, J., Modo, M. (eds) Design and Applications of Nanoparticles in Biomedical Imaging. Springer, Cham. https://doi.org/10.1007/978-3-319-42169-8_3

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