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

第一个可能的转移部位是前哨淋巴结（SNs），可以通过注射染料或放射性示踪剂检测到。在本研究中，我们探讨了SN？靶向经淋巴化疗使用新型磷脂聚合物作为侵入性较小的途径。据报道，SN导航手术中合适的示踪颗粒直径约为50 nm。该新型磷脂聚合物与疏水抗肿瘤试剂紫杉醇（PTX）偶联后，无需添加Cremophor EL等特殊添加剂即可提高其水溶性。该共轭物的大小几乎等于示踪粒子的大小，用于淋巴作图。因此，这种聚合物？局部注射后，PTX偶联物很容易在SNs中积累。将聚合物/PTX偶联液直接注射于雄性东流大鼠盲肠粘膜下层（SM组）和尾静脉（IV组）。将ah130肝癌细胞接种于大鼠盲肠粘膜下层。次日，将聚合物/PTX偶联物沿肿瘤部位（SM组）或尾静脉（IV组）以相同方式周向粘膜下层注射。对照组（n=6）不给药。SM组SN中PTX浓度在各时间点均显著高于IV组。与IV组相比，SM组SNs的平均肿瘤重量明显受到抑制。由此可见，局部注射聚合物/PTX偶联液在动物模型肠系膜SNs淋巴结转移中具有sn特异性分布和抗肿瘤作用。该策略将适用于局限于SNs微转移的各种实体肿瘤的多学科治疗。

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.