Department of Natural Products Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China; Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, China.
Department of Natural Products Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Eur J Med Chem. 2023 Nov 5;259:115693. doi: 10.1016/j.ejmech.2023.115693. Epub 2023 Jul 29.
Epothilone B (Epo B) is a potent antitumor natural product with sub-nanomolar anti-proliferation action against several human cancer cells. However, poor selectivity to tumor cells and unacceptable therapeutic windows of Epo B and its analogs are the major obstacles to their development into clinical drugs. Herein, we present self-assembled nanomicelles based on an amphiphilic carbohydrate-Epo B conjugate that is inactive until converted to active Epo B within the tumor. Four Epo B-Rhamnose conjugates linked via two linkers containing a disulfide bond that is sensitive to GSH were synthesized. Conjugate 34 can self-assemble into nanomicelles with a high concentration of Rha on the surface, allowing for better tumor targeting. After internalization by cancer cells, the disulfide bond can be cleaved in the presence of high levels of GSH to release active Epo B, thereby exhibiting significant anticancer efficiency and selectivity in vitro and in vivo.
埃坡霉素 B（Epo B）是一种强效抗肿瘤天然产物，对多种人类癌细胞具有亚纳摩尔级的抗增殖作用。然而，埃坡霉素 B 及其类似物对肿瘤细胞的选择性差和不可接受的治疗窗是将其开发成临床药物的主要障碍。在此，我们提出了基于两亲性糖 - 埃坡霉素 B 缀合物的自组装纳米胶束，该缀合物在肿瘤内转化为活性埃坡霉素 B 之前是无活性的。合成了通过含有对 GSH 敏感的二硫键的两个接头连接的四个埃坡霉素 B-鼠李糖缀合物。缀合物 34 可以自组装成具有高浓度表面 Rha 的纳米胶束，从而更好地靶向肿瘤。在癌症细胞内化后，在高浓度 GSH 的存在下可以切割二硫键，释放出活性的埃坡霉素 B，从而在体外和体内表现出显著的抗癌效率和选择性。
