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

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 self-assembly 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. [GRAPHICS]

Automated summary

Gut microbial glucuronidase-responsive glycyrrhizin micelles are a type of micelle system that can deliver chemotherapeutic drugs and inhibit P-gp protein, overcoming colon cancer chemotherapy resistance and enhancing its efficacy.