Sentinel node-targeted trans-lymphatic chemotherapy using a phospholipids polymer-paclitaxel conjugate

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Introduction: We have investigated the feasibility of Sentinel node (SN) - targeted trans-lymphatic chemotherapy using novel phospholipids polymer in the present study. 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 aims of this study were to investigate pharmacokinetics of this conjugate after local injection and to evaluate anti-tumor effect in the SN in an animal model. Methods: 1) The polymer/PTX conjugate solution was directly injected into the cecal submucosa (SM group, n=5) and the tail vein (IV group, n=5) of male Donryu rats (3 mg/kg-rat). The SN was defined as the lymph node (LN) in mesocecum stained blue after injection of Lymphazurin. The concentration of PTX in SN was measured at several time points in these 2 groups (6, 12, 24, 48 and 72 hours after injection). 2) Antiproliferative effect in vitro was determined in a MTT assay after continuous exposure of the cells to the conjugate. A431 human epidermoid carcinoma, HT29 human colon carcinoma and others were used in assays. 3) 18 Donryu rats were inoculated with 1.0 x 10⁷AH 130 hepatocellular carcinoma cells reported as a highly metastatic model in SNs. At the next day, polymer/PTX conjugate was injected into submucosal layer of the tumor site (SM group, n=6) or tail vein (IV group, n=6) in the same manner (6 mg/kg-rat). Control group (n=6) received no administration. Six days after the treatment, animals were sacrificed. The weight of SNs and regional draining LNs were measured and examined histopathologically. 4) Three groups were treated on day 1 as above and sacrificed on day 30 to evaluate survival rates. RESULTS: 1)2) In SM group, PTX concentration in SN was significantly higher than that of IV group at every time points (p<0.05). Furthermore, PTX concentration remained above LD50 against A431 more than 24 hours in SN of SM group. 3) Although the average weight of SNs in SM group was increasing compared with the rat of the same weight which is not injecting with the neoplasm, it was significantly lighter than other groups (p<0.05). There was no significant difference in the average weight of SNs among 2 groups of IV and Control. 4) After a follow-up period of 30 days, 3 of 6 rats were alive in SM group, whereas no rat survived in IV group. SM group had a significantly better survival rate than other two groups (p<0.05, log-rank test). In contrast, no statistically significant survival differences could be identified between IV and Control group. CONCLUSIONS: Local injection of the polymer/PTX conjugate solution showed SN-specific distribution and anti-tumor effect in lymph node metastasis in the mesenteric SN in animal model. This strategy would be applicable for the multidisciplinary management of superficial GI cancer with micrometastases limited in SNs distant from the primary lesion.