School of Pharmacy, Iwate Medical University, Iwate, Japan.
The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
Int J Pharm. 2018 Apr 25;541(1-2):206-213. doi: 10.1016/j.ijpharm.2018.02.041. Epub 2018 Feb 24.
This study sought to evaluate the antitumor effects of and elucidate the mechanisms underlying (-)-epigallocatechin-3-O-gallate (EGCG) and polyethyleneglycol (PEG)-modified liposomes. EGCG functions as a target ligand of the 67-kDa laminin receptor (67LR), which is expressed on high-grade tumor cells. An EGCG derivative was synthesized for binding to the end of PEG. Doxorubicin (DOX)-loaded EGCG-PEG-modified liposome (EPL) significantly decreased tumor size in mice bearing high 67LR-high-expressing tumors. Caspase-3 activity, which indicates induction of apoptosis, was also elevated only in the EPL group. The importance of PEG for the antitumor effects of EGCG was noted, as soluble EGCG did not accumulate at a sufficient concentration to exert an apoptotic effect. Moreover, EPL significantly increased caspase-8 activity, suggesting that EPL-induced apoptosis occurred due to caspase-8 activity induced following the binding of EGCG to 67LR as a cell-death ligand. In conclusion, EPL appear to have superior antitumor activity against high 67LR-expressing tumor cells, as the liposomes had dual effects, namely antitumor effects due to the loaded DOX and apoptosis induced by the bound EGCG.
本研究旨在评估 (-)-表没食子儿茶素-3-O-没食子酸酯 (EGCG) 和聚乙二醇 (PEG) 修饰的脂质体的抗肿瘤作用，并阐明其作用机制。EGCG 作为 67 千道尔顿层粘连蛋白受体 (67LR) 的靶配体发挥作用，而 67LR 表达于高级别肿瘤细胞上。本研究合成了一种 EGCG 衍生物，用于与 PEG 的末端结合。载多柔比星（DOX）的 EGCG-PEG 修饰脂质体 (EPL) 可显著减小高表达 67LR 的肿瘤小鼠的肿瘤体积。仅在 EPL 组中，半胱天冬酶-3 活性（表明诱导细胞凋亡）升高。需要注意的是，PEG 对 EGCG 的抗肿瘤作用很重要，因为可溶性 EGCG 不能积聚到足够的浓度来发挥凋亡作用。此外，EPL 还显著增加了半胱天冬酶-8 的活性，表明 EPL 诱导的细胞凋亡是由于 EGCG 与 67LR 结合作为细胞死亡配体后诱导的半胱天冬酶-8 活性所致。总之，EPL 似乎对高表达 67LR 的肿瘤细胞具有更强的抗肿瘤活性，因为这些脂质体具有双重作用，即载 DOX 的抗肿瘤作用和结合的 EGCG 诱导的细胞凋亡作用。
