Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Clinical Oncology; Division of Molecular Oncology, Sapporo Medical University Graduate School of Medicine, Sapporo, Japan.
Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan; Division of Clinical Oncology; Division of Molecular Oncology, Sapporo Medical University Graduate School of Medicine, Sapporo, Japan
J Natl Cancer Inst. 2016 Sep 14;108(9). doi: 10.1093/jnci/djw210. Print 2016 Sep.
Fucose is utilized for the modification of different molecules involved in blood group determination, immunological reactions, and signal transduction pathways. We have recently reported that enhanced activity of the fucosyltransferase 3 and/or 6 promoted TGF-ß-mediated epithelial mesenchymal transition and was associated with increased metastatic potential of colorectal cancer (CRC), suggesting that fucose is required by CRC cells. With this in mind, we examined requirement of L-fucose in CRC cells and developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specific to CRC.
In this study, we first examined the expression of fucosylated proteins in 50 cases of CRC by immunochistochemical staining with biotinylated Aleuria aurantia lectin (AAL). Then we carried out an L-fucose uptake assay using three CRC cell lines. Finally, we developed fucose-bound nanoparticles as vehicles for the delivery of an anticancer drug, SN38, and examined tumor growth inhibition in mouse xenograft model (n = 6 mice per group). All statistical tests were two-sided.
We found a statistically significant relationship between vascular invasion, clinical stage, and intensity score of AAL staining (P ≤ .02). L-fucose uptake assay revealed that L-fucose incorporation, as well as fucosylated protein release, was high in cells rich in fucosylated proteins. L-fucose-bound liposomes effectively delivered Cy5.5 into CRC cells. The excess of L-fucose decreased the efficiency of Cy5.5 uptake through L-fucose-bound liposomes, suggesting an L-fucose receptor dependency. Intravenously injected, L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition (relative tumor growth ratio: no treatment group [NT], 8.29 ± 3.09; SN38-treated group [SN38], 3.53 ± 1.47; liposome-carrying, SN38-treated group [F0], 3.1 ± 1.39; L-fucose-bound, liposome-carrying, SN38-treated group [F50], 0.94 ± 0.89; F50 vs NT, P = .003; F50 vs SN38, P = .02, F50 vs F0, P = .04), as well as prolonging survival of mouse xenograft models (log-rank test, P < .001).
Thus, fucose-bound liposomes carrying anticancer drugs provide a new strategy for the treatment of CRC patients.
岩藻糖被用于修饰不同的分子，这些分子参与血型决定、免疫反应和信号转导途径。我们最近报道，岩藻糖基转移酶 3 和/或 6 的活性增强促进了 TGF-β介导的上皮间质转化，并且与结直肠癌（CRC）的转移潜能增加有关，这表明 CRC 细胞需要岩藻糖。考虑到这一点，我们检查了 CRC 细胞中 L-岩藻糖的需求，并开发了岩藻糖结合的纳米颗粒作为输送特定于 CRC 的抗癌药物的载体。
在这项研究中，我们首先通过生物素化金耳黄伞凝集素（AAL）的免疫组织化学染色检查了 50 例 CRC 中的岩藻糖基化蛋白的表达。然后，我们使用三种 CRC 细胞系进行了 L-岩藻糖摄取测定。最后，我们开发了岩藻糖结合的纳米颗粒作为抗癌药物 SN38 的递送载体，并在小鼠异种移植模型中检查了肿瘤生长抑制（每组 n = 6 只小鼠）。所有统计检验均为双侧检验。
我们发现血管侵犯、临床分期和 AAL 染色强度评分之间存在统计学显著关系（P ≤.02）。L-岩藻糖摄取测定显示，富含岩藻糖基化蛋白的细胞中 L-岩藻糖的掺入以及岩藻糖基化蛋白的释放均很高。岩藻糖结合的脂质体有效地将 Cy5.5 递送至 CRC 细胞。过量的 L-岩藻糖通过岩藻糖结合的脂质体降低了 Cy5.5 摄取的效率，表明存在 L-岩藻糖受体依赖性。静脉注射 SN38 携带的岩藻糖结合脂质体成功递送至 CRC 细胞，介导有效的肿瘤生长抑制（相对肿瘤生长比：无治疗组 [NT]，8.29 ± 3.09；SN38 治疗组 [SN38]，3.53 ± 1.47；载脂蛋白-carrying，SN38 治疗组 [F0]，3.1 ± 1.39；岩藻糖结合，载脂蛋白-carrying，SN38 治疗组 [F50]，0.94 ± 0.89；F50 vs NT，P =.003；F50 vs SN38，P =.02，F50 vs F0，P =.04），并延长了小鼠异种移植模型的存活时间（对数秩检验，P <.001）。
因此，携带抗癌药物的岩藻糖结合脂质体为 CRC 患者的治疗提供了一种新策略。
