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

沿原发灶淋巴引流路线的第一个可能的转移部位称为前哨淋巴结(SN)，使用注射染料或放射性示踪剂可以检测到这些部位。在本研究中，我们研究了SN？使用新型磷脂聚合物作为一种侵入性较小的方法进行靶向跨淋巴化疗。据报道，SN导航手术中示踪剂颗粒的合适尺寸约为50 nm。与疏水性抗肿瘤试剂紫杉醇(PTX)偶联的新型磷脂聚合物，在没有特殊添加剂如乳油EL的情况下，可以提高其水溶性。这种结合物的大小几乎等于淋巴定位示踪剂颗粒的大小。因此，这种聚合物？PTX结合物局部注射后易在三叉神经节内蓄积，将聚合物/PTX结合物直接注入雄性冬雨大鼠盲肠黏膜下层(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。第二天，将聚合物/PTX结合物以相同的方式环行注射到肿瘤部位周围的黏膜下层(SM组)或尾静脉(IV组)。对照组(n=6)不给药，SM组各时间点SN中的PTX浓度均显著高于IV组。SM组SNS平均瘤重明显低于IV组。根据这些数据，局部注射聚合物/PTX结合物溶液在动物模型的肠系膜SNS的淋巴转移中显示出SN特异性的分布和抗肿瘤作用。这一策略将适用于SNS中各种微转移的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.