{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T21:29:53Z","timestamp":1768685393701,"version":"3.49.0"},"reference-count":76,"publisher":"Wiley","issue":"49","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma\u2010related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)\u2010based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma\u2010derived EXs as natural nanocarriers of the positron\u2010emitter copper\u201064 (<jats:sup>64<\/jats:sup>Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with <jats:sup>64<\/jats:sup>Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole\u2010body PET\/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of <jats:sup>64<\/jats:sup>Cu\u2010NODAGA\u2010EXs in metastatic lesions as small as 2\u20133\u00a0mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)\u2010labeled EXs and D\u2010luciferin\u2010loaded EXs. These findings show that tumor\u2010derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.<\/jats:p>","DOI":"10.1002\/smll.202203999","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T02:55:52Z","timestamp":1667271352000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Osteosarcoma\u2010Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9018-2220","authenticated-orcid":false,"given":"Sara F.F.","family":"Almeida","sequence":"first","affiliation":[{"name":"Institute for Nuclear Sciences Applied to Health (ICNAS) and Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"}]},{"given":"Alexandra","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Institute for Nuclear Sciences Applied to Health (ICNAS) and Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra  3000\u2010548 Coimbra Portugal"}]},{"given":"Jos\u00e9","family":"Sereno","sequence":"additional","affiliation":[{"name":"Institute for Nuclear Sciences Applied to Health (ICNAS) and Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Chemistry Department University of Coimbra  3004\u2010535 Coimbra Portugal"}]},{"given":"Hugo R. S.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"}]},{"given":"Mariana","family":"Lapo\u2010Pais","sequence":"additional","affiliation":[{"name":"Institute for Nuclear Sciences Applied to Health (ICNAS) and Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra  3000\u2010548 Coimbra Portugal"}]},{"given":"T\u00e2nia","family":"Martins\u2010Marques","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"}]},{"given":"Teresa","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"}]},{"given":"Rui C.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"},{"name":"Pathology Department Centro Hospitalar e Universit\u00e1rio de Coimbra  3004\u2010561 Coimbra Portugal"}]},{"given":"Catarina","family":"Miranda","sequence":"additional","affiliation":[{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC) University of Coimbra  3004\u2010504 Coimbra Portugal"}]},{"given":"Lu\u00eds P.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC) University of Coimbra  3004\u2010504 Coimbra Portugal"}]},{"given":"Henrique","family":"Gir\u00e3o","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"}]},{"given":"Am\u00edlcar","family":"Falc\u00e3o","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Coimbra  3000\u2010548 Coimbra Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4145-854X","authenticated-orcid":false,"given":"Antero J.","family":"Abrunhosa","sequence":"additional","affiliation":[{"name":"Institute for Nuclear Sciences Applied to Health (ICNAS) and Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT) University of Coimbra  3000\u2010548 Coimbra Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-4129","authenticated-orcid":false,"given":"C\u00e9lia M.","family":"Gomes","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Coimbra Institute for Clinical and Biomedical Research (iCBR) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology Consortium (CIBB) University of Coimbra  3000\u2010548 Coimbra Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC)  3000\u2010075 Coimbra Portugal"}]}],"member":"311","published-online":{"date-parts":[[2022,10,31]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3838"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082130"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971-5851.203513"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2013.11.006"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073817"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ocl.2015.08.022"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/14737140.2018.1413939"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8070727"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-0995-1"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15756"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2019.04.011"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.39434"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.02.020"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11121979"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174435"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010014"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nano.2015.10.012"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S210731"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3402\/jev.v5.32538"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/membranes12010085"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/nano11061481"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.04.016"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.33482"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2019.06.005"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3303"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.203990"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102906"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21020665"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9158319"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.7150\/ntno.51676"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249443"},{"key":"e_1_2_9_32_1","first-page":"1","volume-title":"Reference Module in Chemistry, Molecular Sciences and Chemical Engineering","author":"Crestoni M. E.","year":"2018"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9NR02512J"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.9b00587"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00442"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7NR04128D"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2020.00535"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rechem.2020.100092"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.2174\/1876504101002020026"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11060798"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2013.11.083"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.12.013"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.0c09873"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.3402\/jev.v4.26238"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-020-0573-0"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.8b02587"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2019.10.022"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines6040069"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102191"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201602173"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2009.0674"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S170879"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar800255q"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1039\/C3CS60304K"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21217850"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20051080"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2014.12.009"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nucmedbio.2014.09.009"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.2832"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02691-3"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.37097"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2018.07.007"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2021.01.001"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.38198"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.27891"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.1c00597"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-020-00746-8"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00817"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10030553"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc882"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.07.007"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep13243"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471143030.cb0322s30"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0217732317400132"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.3390\/instruments2030017"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1088\/1748-0221\/9\/10\/C10012"}],"container-title":["Small"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.202203999","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/smll.202203999","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/smll.202203999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T13:44:31Z","timestamp":1692452671000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/smll.202203999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,31]]},"references-count":76,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/smll.202203999"],"URL":"https:\/\/doi.org\/10.1002\/smll.202203999","archive":["Portico"],"relation":{},"ISSN":["1613-6810","1613-6829"],"issn-type":[{"value":"1613-6810","type":"print"},{"value":"1613-6829","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,31]]},"assertion":[{"value":"2022-06-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2203999"}}