Development of novel trans-lymphatic chemotherapy targeted to micrometastasis in sentinel lymph nodes using a phospholipids polymer-paclitaxel conjugate

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The first possible sites of metastasis along the route of lymphatic drainage from the primary lesion are known as sentinel nodes (SNs) and these are detectable using injection of dyes or radioactive tracers. In the present study, we have investigated the feasibility of SN? targeted trans-lymphatic chemotherapy using novel phospholipids polymer as a less invasive approach. The suitable size of tracer particles in SN navigation surgery is reportedly about 50 nm in diameter. The novel phospholipids polymer conjugated with hydrophobic anti-tumor reagent, paclitaxel (PTX), can be enhanced its water-solubility without specific additives such as Cremophor EL. The size of this conjugate is nearly equal to the size of tracer particle for lymphatic mapping. Therefore, this polymer ? PTX conjugate is supposed to be easily accumulated in the SNs after local injection.The polymer/PTX conjugate solution was directly injected into the cecal submucosa (SM group) and the tail vein (IV group) of male Donryu rats. AH 130 hepatocellular carcinoma cells were inoculated into the submucosal layer of cecum of rats. At the next day, polymer/PTX conjugate was injected into submucosal layer in a circumferential manner around the tumor site (SM group) or tail vein (IV group) in the same manner. Control group (n=6) received no administration.PTX concentration in SN of SM group was significantly higher than that of IV group at every time points. The average tumor weight of SNs in SM group was significantly suppressed in comparison with that of IV group. From these data, local injection of the polymer/PTX conjugate solution showed SN-specific distribution and anti-tumor effect in lymph node metastasis in the mesenteric SNs in animal model. This strategy would be applicable for the multidisciplinary management of various solid tumors with micrometastases limited in SNs.