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

使用磷脂聚合物-紫杉醇缀合物开发针对前哨淋巴结微转移的新型经淋巴化疗

基本信息

批准号：
16591352
负责人：
KITAGAWA Yuko
金额：
$ 2.3万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

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.

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)，可以使用注射染料或放射性示踪剂来检测这些部位。在本研究中，我们研究了 SN? 的可行性？使用新型磷脂聚合物作为侵入性较小的方法进行靶向经淋巴化疗。据报道，SN 导航手术中示踪粒子的合适尺寸为直径约 50 nm。新型磷脂聚合物与疏水性抗肿瘤试剂紫杉醇（PTX）缀合，无需特定添加剂（例如Cremophor EL）即可增强其水溶性。该缀合物的大小几乎等于用于淋巴图谱的示踪颗粒的大小。因此，这种聚合物？ PTX结合物被认为在局部注射后很容易在SNs中积聚。将聚合物/PTX结合物溶液直接注射到雄性Donryu大鼠的盲肠粘膜下层（SM组）和尾静脉（IV组）中。将AH 130肝癌细胞接种到大鼠盲肠粘膜下层。第二天，以相同方式将聚合物/PTX缀合物以圆周方式注射到肿瘤部位（SM组）或尾静脉（IV组）周围的粘膜下层。对照组(n=6)不给药。SM组SN中PTX浓度各时间点均显着高于IV组。 SM组中SN的平均肿瘤重量与IV组相比显着抑制。从这些数据来看，局部注射聚合物/PTX缀合物溶液在动物模型中显示出肠系膜SN的淋巴结特异性分布和抗肿瘤作用。该策略将适用于对局限于 SN 的微转移的各种实体瘤的多学科治疗。