Treatment of false‐negative metastatic lymph nodes by a lymphatic drug delivery system with 5‐fluorouracil

Metastatic lymph nodes (LNs) may be the origin of systemic metastases. It will be important to develop a strategy that prevents systemic metastasis by treating these LNs at an early stage. False‐negative metastatic LNs, which are found during the early stage of metastasis development, are those that contain tumor cells but have a size and shape similar to LNs that do not host tumor cells. Here, we show that 5‐fluorouracil (5‐FU), delivered by means of a novel lymphatic drug delivery system (LDDS), can treat LNs with false‐negative metastases in a mouse model. The effects of 5‐FU on four cell lines were investigated using in vitro cytotoxicity and cell survival assays. The therapeutic effects of LDDS‐administered 5‐FU on false‐negative metastatic LNs were evaluated using bioluminescence imaging, high‐frequency ultrasound (US), and histology in MHX10/Mo‐lpr/lpr mice. These experimental animals develop LNs that are similar in size to human LNs. We found that all cell lines showed sensitivity to 5‐FU in the in vitro assays. Furthermore, a concentration‐dependent effect of 5‐FU to inhibit tumor growth was observed in tumor cells with low invasive growth characteristics, although a significant reduction in metastatic LN volume was not detected in MHX10/Mo‐lpr/lpr mice. Adverse effects of 5‐FU were not detected. 5‐Fluorouracil administration with a LDDS is an effective treatment method for false‐negative metastatic LNs. We anticipate that the delivery of anticancer drugs by a LDDS will be of great benefit in the prevention and treatment of cancer metastasis via LNs.