Abstract
In vivo distribution of extracellular vesicles (EVs) are important in clinical application. Recently, tracking methods have been developed to monitor EVs in vivo. It ranged from fluorescence imaging to clinically available radionuclide imaging or magnetic resonance imaging. Each method has pros and cons in terms of capability of quantification, penetration depth, availability and clinical translatability. We introduce currently available labeling methods for imaging and their advantages and disadvantages. These imaging methods have elucidated the in vivo biodistribution of EVs. However, technical factors such as isolation, labeling methods and administration methods as well as biological factors including cell sources have resulted in variability of biodistribution patterns. We also review biodistribution results of EVs and what impacts on biodistribution.
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A.V. Vlassov, S. Magdaleno, R. Setterquist, R. Conrad, Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim. Biophys. Acta 1820(7), 940–948 (2012)
Y. Lee, S. El Andaloussi, M.J. Wood, Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum. Mol. Genet. 21(R1), R125–R134 (2012)
Y. Sun, J. Liu, Potential of cancer cell-derived exosomes in clinical application: a review of recent research advances. Clin. Ther. 36(6), 863–872 (2014)
D. Sun, X. Zhuang, S. Zhang, Z.-B. Deng, W. Grizzle, D. Miller et al., Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv. Drug Deliv. Rev. 65(3), 342–347 (2013)
M. Colombo, G. Raposo, C. Thery, Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255–289 (2014)
A.K.A. Silva, R. Di Corato, T. Pellegrino, S. Chat, G. Pugliese, N. Luciani et al., Cell-derived vesicles as a bioplatform for the encapsulation of theranostic nanomaterials. Nanoscale 5(23), 11374–11384 (2013)
A.K. Silva, N. Luciani, F. Gazeau, K. Aubertin, S. Bonneau, C. Chauvierre et al., Combining magnetic nanoparticles with cell derived microvesicles for drug loading and targeting. Nanomedicine 11(3), 645–655 (2015)
A.K. Silva, J. Kolosnjaj-Tabi, S. Bonneau, I. Marangon, N. Boggetto, K. Aubertin et al., Magnetic and photoresponsive theranosomes: translating cell-released vesicles into smart nanovectors for cancer therapy. ACS Nano. 7(6), 4954–4966 (2013)
C.P. Lai, O. Mardini, M. Ericsson, S. Prabhakar, C.A. Maguire, J.W. Chen et al., Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 8(1), 483–494 (2014)
Y. Takahashi, M. Nishikawa, H. Shinotsuka, Y. Matsui, S. Ohara, T. Imai et al., Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J. Biotechnol. 165(2), 77–84 (2013)
J.L. Hood, R.S. San, S.A. Wickline, Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71(11), 3792–3801 (2011)
S. Ohno, M. Takanashi, K. Sudo, S. Ueda, A. Ishikawa, N. Matsuyama et al., Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21(1), 185–191 (2013)
T. Tian, Y.L. Zhu, F.H. Hu, Y.Y. Wang, N.P. Huang, Z.D. Xiao, Dynamics of exosome internalization and trafficking. J. Cell. Physiol. 228(7), 1487–1495 (2013)
T. Smyth, M. Kullberg, N. Malik, P. Smith-Jones, M.W. Graner, T.J. Anchordoquy, Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control Release. 199, 145–155 (2015)
T. Tian, Y. Wang, H. Wang, Z. Zhu, Z. Xiao, Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J. Cell. Biochem. 111(2), 488–496 (2010)
K. Laulagnier, H. Vincent-Schneider, S. Hamdi, C. Subra, D. Lankar, M. Record, Characterization of exosome subpopulations from RBL-2H3 cells using fluorescent lipids. Blood Cells Mol. Dis. 35(2), 116–121 (2005)
D. Sun, X. Zhuang, X. Xiang, Y. Liu, S. Zhang, C. Liu et al., A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18(9), 1606–1614 (2010)
C. Grange, M. Tapparo, S. Bruno, D. Chatterjee, P.J. Quesenberry, C. Tetta et al., Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int. J. Mol. Med. 33(5), 1055–1063 (2014)
M. Mittelbrunn, C. Gutierrez-Vazquez, C. Villarroya-Beltri, S. Gonzalez, F. Sanchez-Cabo, M.A. Gonzalez et al., Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011)
A. Suetsugu, K. Honma, S. Saji, H. Moriwaki, T. Ochiya, R.M. Hoffman, Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Adv. Drug Deliv. Rev. 65(3), 383–390 (2013)
C.P.-K. Lai, X.O. Breakefield, Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol. 3, 228–242 (2012)
C.P. Lai, E.Y. Kim, C.E. Badr, R. Weissleder, T.R. Mempel, B.A. Tannous et al., Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat. Commun. 6, 7029 (2015)
M. Morishita, Y. Takahashi, M. Nishikawa, K. Sano, K. Kato, T. Yamashita et al., 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(2), 705–713 (2015)
H. Choi, S.C. Jang, M.Y. Yoo, J.Y. Park, N.E. Choi, H.J. Oh et al., Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using 99mTc-HMPAO. Sci. Rep. 5, 15636 (2015)
Z. Varga, I. Gyurkó, K. Pálóczi, E.I. Buzás, I. Horváth, N. Hegedűs et al., Radiolabeling of extracellular vesicles with 99mTc for quantitative in vivo imaging studies. Cancer Biother. Radiopharm. 31(5), 168–173 (2016)
L. Hu, S.A. Wickline, J.L. Hood, Magnetic resonance imaging of melanoma exosomes in lymph nodes. Magn. Reson. Med. 74(1), 266–271 (2015)
A. Busato, R. Bonafede, P. Bontempi, I. Scambi, L. Schiaffino, D. Benati et al., Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: a new method to obtain labeled exosomes. Int. J. Nanomedicine 11, 2481 (2016)
S.A. Kooijmans, S. Stremersch, K. Braeckmans, S.C. de Smedt, A. Hendrix, M.J. Wood et al., Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control Release. 172(1), 229–238 (2013)
R.C. Lai, T.S. Chen, S.K. Lim, Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med. 6(4), 481–492 (2011)
L. Timmers, S.K. Lim, I.E. Hoefer, F. Arslan, R.C. Lai, A.A. van Oorschot et al., Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res. 6(3), 206–214 (2011)
S. Gatti, S. Bruno, M.C. Deregibus, A. Sordi, V. Cantaluppi, C. Tetta et al., Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol. Dial. Transplant. 26(5), 1474–1483 (2011)
S. Bian, L. Zhang, L. Duan, X. Wang, Y. Min, H. Yu, Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J. Mol. Med. Berl. 92(4), 387–397 (2014)
L. Kilpinen, U. Impola, L. Sankkila, I. Ritamo, M. Aatonen, S. Kilpinen et al., Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J. Extracell. Vesicles 2(1), 21927 (2013)
H. Peinado, M. Alečković, S. Lavotshkin, I. Matei, B. Costa-Silva, G. Moreno-Bueno et al., Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18(6), 883–891 (2012)
O.P. Wiklander, J.Z. Nordin, A. O’Loughlin, Y. Gustafsson, G. Corso, I. Mäger et al., Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 4(1), 26316 (2015)
K.W. Witwer, E.I. Buzas, L.T. Bemis, A. Bora, C. Lässer, J. Lötvall et al., Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2(1), 20360 (2013)
A.N. Böing, E. Van Der Pol, A.E. Grootemaat, F.A. Coumans, A. Sturk, R. Nieuwland, Single-step isolation of extracellular vesicles by size-exclusion chromatography. J. Extracell. Vesicles 3(1), 23430 (2014)
J.Z. Nordin, Y. Lee, P. Vader, I. Mäger, H.J. Johansson, W. Heusermann et al., Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomedicine 11(4), 879–883 (2015)
R. Linares, S. Tan, C. Gounou, N. Arraud, A.R. Brisson, High-speed centrifugation induces aggregation of extracellular vesicles. J. Extracell. Vesicles 4(1), 29509 (2015)
R. van der Meel, M.H. Fens, P. Vader, W.W. van Solinge, O. Eniola-Adefeso, R.M. Schiffelers, Extracellular vesicles as drug delivery systems: lessons from the liposome field. J. Control Release. 195, 72–85 (2014)
T.A. Shtam, R.A. Kovalev, E.Y. Varfolomeeva, E.M. Makarov, Y.V. Kil, M.V. Filatov, Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun. Signal. 11(1), 88 (2013)
H. Choi, Y.-S. Lee, D.W. Hwang, D.S. Lee, Translational radionanomedicine: a clinical perspective. Eur. J. Nanomed. 8(2), 71–84 (2016)
H. Choi, D.S. Lee, Illuminating the physiology of extracellular vesicles. Stem Cell Res. Ther. 7(1), 55 (2016)
S.M. Moghimi, A.C. Hunter, J.C. Murray, Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol. Rev. 53(2), 283–318 (2001)
S.-D. Li, L. Huang, Pharmacokinetics and biodistribution of nanoparticles. Mol. Pharm. 5(4), 496–504 (2008)
S. Reske, Recent advances in bone marrow scanning. Eur. J. Nucl. Med. Mol. Imaging 18(3), 203–221 (1991)
H. Sarin, Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J. Angiogenes Res. 2(1), 14 (2010)
M.C. Garnett, P. Kallinteri, Nanomedicines and nanotoxicology: some physiological principles. Occup. Med. Lond. 56(5), 307–311 (2006)
S.J. Gould, G. Raposo, As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles 2(1), 20389 (2013)
S. El Andaloussi, I. Mäger, X.O. Breakefield, M.J. Wood, Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 12(5), 347 (2013)
S. Rana, S. Yue, D. Stadel, M. Zoller, Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int. J. Biochem. Cell Biol. 44(9), 1574–1584 (2012)
S. Rana, M. Zöller, Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis. Biochem. Soc. Trans. 39(2), 559–562 (2011)
L. Lattanzi, M. Federico, A strategy of antigen incorporation into exosomes: comparing cross-presentation levels of antigens delivered by engineered exosomes and by lentiviral virus-like particles. Vaccine 30(50), 7229–7237 (2012)
R.C. Lai, S.S. Tan, R.W.Y. Yeo, A.B.H. Choo, A.T. Reiner, Y. Su et al., MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. J. Extracell. Vesicles 5(1), 29828 (2016)
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Choi, H., Lee, D.S. (2018). Endogenous Radionanomedicine: Biodistribution and Imaging. In: Lee, D. (eds) Radionanomedicine. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-67720-0_8
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DOI: https://doi.org/10.1007/978-3-319-67720-0_8
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