{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:59:24Z","timestamp":1784897964882,"version":"3.55.0"},"reference-count":51,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation (NRF) from Ministry of Science and ICT, Republic of Korea","award":["2011-0030001"],"award-info":[{"award-number":["2011-0030001"]}]},{"name":"National Research Foundation (NRF) from Ministry of Science and ICT, Republic of Korea","award":["2017R1A2B4012813"],"award-info":[{"award-number":["2017R1A2B4012813"]}]},{"name":"National Research Foundation (NRF) from Ministry of Science and ICT, Republic of Korea","award":["2019R1I1A1A01057845"],"award-info":[{"award-number":["2019R1I1A1A01057845"]}]},{"name":"National Research Foundation (NRF) from Ministry of Science and ICT, Republic of Korea","award":["2020R1A2C2011695"],"award-info":[{"award-number":["2020R1A2C2011695"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There has been considerable interest in the clinical use of exosomes as delivery vehicles for treatments as well as for promising diagnostic biomarkers, but the physiological distribution of exosomes must be further elucidated to validate their efficacy and safety. Here, we aimed to develop novel methods to monitor exosome biodistribution in vivo using positron emission tomography (PET) and optical imaging. Exosomes were isolated from cultured mouse breast cancer cells and labeled for PET and optical imaging. In mice, radiolabeled and fluorescently labeled exosomes were injected both via lymphatic and hematogenous metastatic routes. PET and fluorescence images were obtained and quantified. Radioactivity and fluorescence intensity of ex vivo organs were measured. PET signals from exosomes in the lymphatic metastatic route were observed in the draining sentinel lymph nodes. Immunohistochemistry revealed greater exosome uptake in brachial and axillary versus inguinal lymph nodes. Following administration through the hematogenous metastasis pathway, accumulation of exosomes was clearly observed in the lungs, liver, and spleen. Exosomes from tumor cells were successfully labeled with 64Cu (or 68Ga) and fluorescence and were visualized via PET and optical imaging, suggesting that this simultaneous and rapid labeling method could provide valuable information for further exosome translational research and clinical applications.<\/jats:p>","DOI":"10.3390\/ijms21217850","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T20:51:00Z","timestamp":1603399860000},"page":"7850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Identification of Lymphatic and Hematogenous Routes of Rapidly Labeled Radioactive and Fluorescent Exosomes through Highly Sensitive Multimodal Imaging"],"prefix":"10.3390","volume":"21","author":[{"given":"Kyung Oh","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-5606","authenticated-orcid":false,"given":"Young-Hwa","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Medical Research Center, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 08826, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seock-Jin","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul-Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyeon","family":"Rhee","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillem","family":"Pratx","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Division of Medical Physics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"June-Key","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyewon","family":"Youn","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Medical Research Center, Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul 03080, Korea"},{"name":"Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul 08826, Korea"},{"name":"Cancer Imaging Center, Seoul National University Hospital, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri855","article-title":"Exosomes: Composition, biogenesis and function","volume":"2","author":"Thery","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: Exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.bcp.2011.02.011","article-title":"Exosomes as intercellular signalosomes and pharmacological effectors","volume":"81","author":"Record","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14240","DOI":"10.3390\/ijms140714240","article-title":"Intercellular Communication by Exosome-Derived microRNAs in Cancer","volume":"14","author":"Hannafon","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.2174\/1574889810666150702124059","article-title":"Exosome-based strategies for Diagnosis and Therapy","volume":"10","author":"Urbanelli","year":"2015","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1517\/14712598.2012.680018","article-title":"Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors","volume":"12","year":"2012","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9899","DOI":"10.18632\/oncotarget.14247","article-title":"Visualization of exosome-mediated miR-210 transfer from hypoxic tumor cells","volume":"8","author":"Jung","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.jconrel.2011.11.021","article-title":"Microvesicles and exosomes: Opportunities for cell-derived membrane vesicles in drug delivery","volume":"161","author":"Vader","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/mt.2012.180","article-title":"Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells","volume":"21","author":"Ohno","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7698","DOI":"10.1021\/nn402232g","article-title":"Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors","volume":"7","author":"Jang","year":"2013","journal-title":"ACS Nano"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nbt.1830","article-title":"SiRNA delivery with exosome nanoparticles","volume":"29","author":"Schlee","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9158319","DOI":"10.1155\/2017\/9158319","article-title":"Current perspectives on in vivo noninvasive tracking of extracellular vesicles with molecular imaging","volume":"2017","author":"Gangadaran","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_14","first-page":"2481","article-title":"Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide-labeled exosomes from stem cells: A new method to obtain labeled exosomes","volume":"11","author":"Busato","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.biomaterials.2018.05.048","article-title":"Development and MPI tracking of novel hypoxia-targeted theranostic exosomes","volume":"177","author":"Jung","year":"2018","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1002\/wnan.1594","article-title":"Advances in imaging strategies for in vivo tracking of exosomes","volume":"12","author":"Betzer","year":"2020","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.addr.2012.08.007","article-title":"Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models","volume":"65","author":"Suetsugu","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jbiotec.2013.03.013","article-title":"Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection","volume":"165","author":"Takahashi","year":"2013","journal-title":"J. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1158\/0008-5472.CAN-10-4455","article-title":"Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis","volume":"71","author":"Hood","year":"2011","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7029","DOI":"10.1038\/ncomms8029","article-title":"Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters","volume":"6","author":"Lai","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/smll.201401803","article-title":"In vivo kinetic biodistribution of nano-sized outer membrane vesicles derived from bacteria","volume":"11","author":"Jang","year":"2015","journal-title":"Small"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1016\/j.biomaterials.2013.11.083","article-title":"A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy","volume":"35","author":"Tian","year":"2014","journal-title":"Biomaterials"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"164","DOI":"10.2967\/jnumed.107.045955","article-title":"Molecular-genetic imaging based on reporter gene expression","volume":"49","author":"Kang","year":"2008","journal-title":"J. Nucl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jconrel.2014.12.013","article-title":"Biodistribution and delivery efficiency of unmodified tumor-derived exosomes","volume":"199","author":"Smyth","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/jps.24251","article-title":"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","volume":"104","author":"Morishita","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15636","DOI":"10.1038\/srep15636","article-title":"Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using (99m)Tc-HMPAO","volume":"5","author":"Hwang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1002\/smll.201100927","article-title":"Tumor targeting and imaging using cyclic RGD-PEGylated gold nanoparticle probes with directly conjugated iodine-125","volume":"7","author":"Kim","year":"2011","journal-title":"Small"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1046\/j.1365-313x.2001.01071.x","article-title":"Quantitative in vivo measurement of glutathione in Arabidopsis cells","volume":"27","author":"Meyer","year":"2001","journal-title":"Plant J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2967\/jnumed.108.057182","article-title":"Standards for PET image acquisition and quantitative data analysis","volume":"50","author":"Boellaard","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1111\/j.1600-0854.2008.00734.x","article-title":"Exosome function: From tumor immunology to pathogen biology","volume":"9","author":"Schorey","year":"2008","journal-title":"Traffic"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s10555-013-9441-9","article-title":"Exosomes in cancer development, metastasis, and drug resistance: A comprehensive review","volume":"32","author":"Azmi","year":"2013","journal-title":"Cancer Metastasis Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc865","article-title":"Dissemination and growth of cancer cells in metastatic sites","volume":"2","author":"Chambers","year":"2002","journal-title":"Nat. Rev. Cancer."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nrc1098","article-title":"The pathogenesis of cancer metastasis: The \u2019seed and soil\u2019 hypothesis revisited","volume":"3","author":"Fidler","year":"2003","journal-title":"Nat. Rev. Cancer."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"437","DOI":"10.7150\/thno.3645","article-title":"THERANOSTICS: From molecular imaging using Ga-68 labeled tracers and PET\/CT to personalized radionuclide therapy-The Bad Berka experience","volume":"2","author":"Baum","year":"2012","journal-title":"Theranostics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"94","DOI":"10.2174\/1874471008666150313114644","article-title":"Theranostic applications of lutetium-177 in radionuclide therapy","volume":"9","author":"Das","year":"2016","journal-title":"Curr. Radiopharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2217\/nnm.11.94","article-title":"Development and in vivo imaging of PET\/MRI nanoprobe with enhanced NIR fluorescence by dye encapsulation","volume":"7","author":"Kim","year":"2012","journal-title":"Nanomedicine (Lond)"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/nprot.2012.131","article-title":"Exosome-mediated delivery of siRNA in vitro and in vivo","volume":"7","author":"Lee","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1158\/0008-5472.CAN-07-0520","article-title":"Tumor-released microvesicles as vehicles of immunosuppression","volume":"67","author":"Valenti","year":"2007","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/nrc1717","article-title":"The multiple uses of fluorescent proteins to visualize cancer in vivo","volume":"5","author":"Hoffman","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrc3304","article-title":"Metastasis. Exosomes drive premetastatic niche formation","volume":"12","author":"Alderton","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/ncb3169","article-title":"Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver","volume":"17","author":"Aiello","year":"2015","journal-title":"Nat. Cell. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/nm.2775","article-title":"Melanoma exosomes: Messengers of metastasis","volume":"18","author":"Somasundaram","year":"2012","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1593\/neo.09822","article-title":"CD44v6 dependence of premetastatic niche preparation by exosomes","volume":"11","author":"Jung","year":"2009","journal-title":"Neoplasia"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nature15756","article-title":"Tumour exosome integrins determine organotropic metastasis","volume":"527","author":"Hoshino","year":"2015","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1021\/nn404945r","article-title":"Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter","volume":"8","author":"Lai","year":"2014","journal-title":"ACS Nano"},{"key":"ref_46","first-page":"609","article-title":"Cell-cell and cell-stromal interactions in breast cancer invasion and metastasis (review)","volume":"11","author":"Jones","year":"1997","journal-title":"Int. J. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1703074","DOI":"10.1002\/adfm.201703074","article-title":"Exosome as a vehicle for delivery of membrane protein therapeutics, PH20, for enhanced tumor penetration and antitumor efficacy","volume":"28","author":"Hong","year":"2018","journal-title":"Adv. Funct. Mater."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Gilligan, K.E., and Dwyer, R.M. (2017). Engineering exosomes for cancer therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms18061122"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/aps.2017.12","article-title":"Engineering exosomes as refined biological nanoplatforms for drug delivery","volume":"38","author":"Luan","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.nano.2015.09.011","article-title":"Designer exosomes as next-generation cancer immunotherapy","volume":"12","author":"Bell","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"117","DOI":"10.21037\/atm.2017.01.47","article-title":"Is the exosome a potential target for cancer immunotherapy?","volume":"5","author":"Akihiko","year":"2017","journal-title":"Ann. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/7850\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:26:32Z","timestamp":1760178392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/7850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,22]]},"references-count":51,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21217850"],"URL":"https:\/\/doi.org\/10.3390\/ijms21217850","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,22]]}}}