用于增强结肠癌化疗的肠道菌群葡萄糖醛酸酶响应甘草酸胶束

Gut Microbial Glucuronidase-responsive Glycyrrhizin Micelles for Enhanced Colon Cancer Chemotherapy

肿瘤细胞表面过表达P-糖蛋白(P-gp)是导致肿瘤化疗耐药的重要原因.抑制P-gp表达能有效增强化疗效果.为克服结肠癌化疗耐药,本研究设计、制备了一种肠道菌群葡萄糖醛酸酶响应的甘草酸胶束用于递送化疗药物和原位产生P-gp抑制剂.通过自组装,甘草酸(glycyrrhizin,GL)形成胶束,包载疏水性药物阿霉素(doxorubicin,DOX);在GL胶束表面静电交联正电性壳聚糖(chitosan,CS),构建DOX@GLCS胶束.在原位结肠癌小鼠模型中,口服DOX@GLCS胶束后,其在胃和小肠中保持稳定,在富含细菌的结肠和肿瘤区域被特异性降解,释放化疗药物阿霉素.同时,细菌分泌的葡萄糖醛酸酶可以转化GL生成P-gp抑制剂甘草次酸(glycyrrhetinic acid,GA),抑制肿瘤细胞P-gp表达,增加药物的细胞内浓度.经DOX@GLCS治疗后,小鼠肿瘤负荷明显降低,受损肠道黏膜得到修复.该肠道菌群响应释药策略为克服结肠癌化疗耐药提供了一种新思路.

Although chemotherapy is currently the most widely used treatment for colon cancer,it is still severely limited by poor therapeutic efficacy and inevitable side effects.Specially,tumor cells gradually appear insensitive for chemotherapeutics after repeated drug mediation.The overexpression of P-glycoprotein(P-gp)in tumor cells,which significantly reduces intracellular drug concentration,is the most popular cause of chemotherapy resistance.Here,we designed and prepared gut microbial glucuronidase-responsive glycyrrhizin micelles for delivery of a chemotherapeutic drug and in situ generation of P-gp inhibitor to overcome colon cancer chemotherapy resistance and to enhance the chemotherapy effect.Glycyrrhizin(GL)micelles prepared by selfassembly were used to load hydrophobic drug doxorubicin(DOX).Sequentially,chitosan(CS)was electrostatically crosslinked on the surface of GL micelles to construct DOX@GLCS micelles.The results showed that micelles were about 165 nm with promising dispersibility and stability.With the presence of glucuronidase secreted by gut microbes,DOX@GLCS micelles were degraded to release DOX.Meanwhile,GL was converted into glycyrrhetinic acid(GA),which was a potent P-gp inhibitor to decline P-gp expression and enhance intracellular drug accumulation.Compared to free DOX,DOX@GLCS micelles exerted suprior cytotoxicity to colon cancer CT26 cells as well as DOX-ressitant CT26 cells.In two orthotopic colon cancer-bearing mice models,oral administration of DOX@GLCS micelles significantly inhibited tumoral P-gp expression and suppressed tumor growth.Moreover,owing to the regulatory effect of prebiotic chitosan,DOX@GLCS treatment effecively repaired damaged intestinal mucosa.Overall,this gut microbiota-responsive drug delivery system provides a new perspective for augmented CRC chemotherapy.