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However, only a small fraction of an intravenously administered anti\u2010cancer drug enters the lymphatic system to reach metastatic lymph nodes (<jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>). Here, we show that the enhanced permeability and retention (<jats:styled-content style=\"fixed-case\">EPR<\/jats:styled-content>) effect is not induced during the early stages of <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> metastasis. Luciferase\u2010expressing tumor cells were injected into the subiliac <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> of the <jats:styled-content style=\"fixed-case\">MXH<\/jats:styled-content>10\/Mo\u2010<jats:italic>lpr<\/jats:italic>\/<jats:italic>lpr<\/jats:italic> mouse to induce metastasis to the proper axillary <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">PALN<\/jats:styled-content>). <jats:italic>In vivo<\/jats:italic> biofluorescence imaging was used to confirm metastasis induction and to quantify the <jats:styled-content style=\"fixed-case\">EPR<\/jats:styled-content> effect, measured as <jats:styled-content style=\"fixed-case\">PALN<\/jats:styled-content> accumulation of intravenously injected indocyanine green (<jats:styled-content style=\"fixed-case\">ICG<\/jats:styled-content>) liposomes. <jats:styled-content style=\"fixed-case\">PALN<\/jats:styled-content> blood vessel volume changes were measured by contrast\u2010enhanced high\u2010frequency ultrasound imaging. The volume and density of blood vessels in the <jats:styled-content style=\"fixed-case\">PALN<\/jats:styled-content> increased until day\u00a029 after inoculation, whereas the <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> volume remained constant. <jats:styled-content style=\"fixed-case\">ICG<\/jats:styled-content> retention was first detected on day\u00a029 post\u2010inoculation. While <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>31\u2010positive cells increased up to day\u00a029 post\u2010inoculation, \u03b1\u2010smooth muscle actin\u2010positive cells were detected on day\u00a029 post\u2010inoculation for the first time. These results suggest that the <jats:styled-content style=\"fixed-case\">EPR<\/jats:styled-content> effect was not induced in the early stages of <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> metastasis. The development of an alternative drug delivery system, independent of the <jats:styled-content style=\"fixed-case\">EPR<\/jats:styled-content> effect, is required for the treatment of <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> metastasis.<\/jats:p>","DOI":"10.1111\/cas.13206","type":"journal-article","created":{"date-parts":[[2017,2,17]],"date-time":"2017-02-17T07:44:51Z","timestamp":1487317491000},"page":"846-852","source":"Crossref","is-referenced-by-count":54,"title":["Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis"],"prefix":"10.1111","volume":"108","author":[{"given":"Mamoru","family":"Mikada","sequence":"first","affiliation":[{"name":"Laboratory of Biomedical Engineering for Cancer Tohoku University Aoba, Sendai Japan"},{"name":"Biomedical Engineering Cancer Research Center Graduate School of Biomedical Engineering Tohoku University Aoba, Sendai 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Tohoku University Aoba, Sendai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maya","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnosis Tohoku University Hospital Aoba, Sendai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Engineering for Cancer Tohoku University Aoba, Sendai Japan"},{"name":"Biomedical Engineering Cancer Research Center Graduate School of Biomedical Engineering Tohoku University Aoba, Sendai Japan"},{"name":"Department of Oral and Maxillofacial Surgery Tohoku University Hospital Aoba, Sendai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4727-9558","authenticated-orcid":false,"given":"Tetsuya","family":"Kodama","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Engineering for Cancer Tohoku University Aoba, 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