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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591352/
• 关键词: Sentinel node; Micrometastasis; AH130; MPC polymer; 微小転移; Drug delivery system; リンパ節転移; 抗腫瘍化学療法; リンパ系; MPC polymer; Sentinel Node; AH130; Sentinel node; Micrometastasis; AH130; MPC polymer; 微小転移; Drug delivery system; リンパ節転移; 抗腫瘍化学療法; リンパ系; MPC polymer; Sentinel Node; AH130

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.

从原发性病变的淋巴引流途径沿着淋巴引流途径的第一个可能的位点称为前哨节点（SNS），可以通过注射染料或放射性示踪剂来检测这些淋巴结。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一种侵入性的方法，靶向跨淋巴化疗。据报道，SN导航手术中的示踪剂颗粒的合适尺寸约为直径约50 nm。与疏水抗肿瘤试剂，紫杉醇（PTX）结合的新型磷脂聚合物可以增强其水溶性，而无需特定的添加剂，例如Cremophor El。该偶联物的大小几乎等于用于淋巴图映射的示踪剂颗粒的大小。因此，这个聚合物？局部注射后，PTX结合物被认为很容易在SNS中积聚。聚合物/PTX共轭溶液直接注射到Cecal subsucosa（SM组）和雄性Donryu大鼠的尾静脉（IV组）。 AH 130肝细胞癌细胞被接种到大鼠塞库姆粘膜下层中。在第二天，以相同方式将聚合物/PTX结合物以周围的肿瘤部位（SM组）或尾静脉（IV组）周围的方式注入粘膜下层。对照组（n = 6）未收到给药。在每个时间点，SN组的SN组的PTX浓度显着高于IV组的PTX浓度。与IV组相比，SM组中SNS的平均肿瘤重量受到显着抑制。从这些数据中，聚合物/PTX偶联物溶液的局部注入在动物模型的肠系膜SNS中显示出Sn特异性分布和抗肿瘤效应。该策略适用于SNS中有限的各种实体瘤的多学科管理。