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It will be important to develop a strategy that prevents systemic metastasis by treating these <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s at an early stage. False\u2010negative metastatic <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s that do not host tumor cells. Here, we show that 5\u2010fluorouracil (5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content>), delivered by means of a novel lymphatic drug delivery system (<jats:styled-content style=\"fixed-case\">LDDS<\/jats:styled-content>), can treat <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s with false\u2010negative metastases in a mouse model. The effects of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of <jats:styled-content style=\"fixed-case\">LDDS<\/jats:styled-content>\u2010administered 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> on false\u2010negative metastatic <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s were evaluated using bioluminescence imaging, high\u2010frequency ultrasound (<jats:styled-content style=\"fixed-case\">US<\/jats:styled-content>), and histology in <jats:styled-content style=\"fixed-case\">MHX<\/jats:styled-content>10\/Mo\u2010<jats:italic>lpr<\/jats:italic>\/<jats:italic>lpr<\/jats:italic> mice. These experimental animals develop <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s that are similar in size to human <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s. We found that all cell lines showed sensitivity to 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> in the in vitro assays. Furthermore, a concentration\u2010dependent effect of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content> volume was not detected in <jats:styled-content style=\"fixed-case\">MHX<\/jats:styled-content>10\/Mo\u2010<jats:italic>lpr<\/jats:italic>\/<jats:italic>lpr<\/jats:italic> mice. Adverse effects of 5\u2010<jats:styled-content style=\"fixed-case\">FU<\/jats:styled-content> were not detected. 5\u2010Fluorouracil administration with a <jats:styled-content style=\"fixed-case\">LDDS<\/jats:styled-content> is an effective treatment method for false\u2010negative metastatic <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s. We anticipate that the delivery of anticancer drugs by a <jats:styled-content style=\"fixed-case\">LDDS<\/jats:styled-content> will be of great benefit in the prevention and treatment of cancer metastasis via <jats:styled-content style=\"fixed-case\">LN<\/jats:styled-content>s.<\/jats:p>","DOI":"10.1002\/cam4.2125","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T02:51:44Z","timestamp":1554346304000},"page":"2241-2251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Treatment of false\u2010negative metastatic lymph nodes by a lymphatic drug delivery system with 5\u2010fluorouracil"],"prefix":"10.1002","volume":"8","author":[{"given":"Honoka","family":"Fujii","sequence":"first","affiliation":[{"name":"Laboratory of Biomedical Engineering for Cancer Graduate School of Biomedical Engineering Tohoku University Aoba, Sendai Miyagi Japan"},{"name":"Biomedical Engineering Cancer 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