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

韩子意; 白雪峰; 王钰璋; 陈其文; 张先正

doi:10.11777/j.issn1000-3304.2022.22021

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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

研究论文 | 更新时间：2024-10-08

- 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
- 高分子学报 2022年53卷第6期页码：626-635
- 作者机构：
  
  武汉大学生物医用高分子材料教育部重点实验室化学与分子科学学院武汉 430072
- 作者简介：
  
  E-mail: xz-zhang@whu.edu.cn
- 基金信息：
  
  国家重点基础研究发展计划(2019YFA0905603);国家自然科学基金(基金号 ┣22135005;51833007);21721005┫
- DOI：10.11777/j.issn1000-3304.2022.22021
  中图分类号：
- 纸质出版日期：2022-06-20，
  
  网络出版日期：2022-04-22，
  
  收稿日期：2022-01-18，
  
  录用日期：2022-03-04
- 稿件说明：
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韩子意,白雪峰,王钰璋等.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[J].高分子学报,2022,53(06):626-635.

Han Zi-yi,Bai Xue-feng,Wang Yu-zhang,et al.Gut Microbial Glucuronidase-responsive Glycyrrhizin Micelles for Enhanced Colon Cancer Chemotherapy[J].ACTA POLYMERICA SINICA,2022,53(06):626-635.
韩子意,白雪峰,王钰璋等.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[J].高分子学报,2022,53(06):626-635. DOI： 10.11777/j.issn1000-3304.2022.22021.

Han Zi-yi,Bai Xue-feng,Wang Yu-zhang,et al.Gut Microbial Glucuronidase-responsive Glycyrrhizin Micelles for Enhanced Colon Cancer Chemotherapy[J].ACTA POLYMERICA SINICA,2022,53(06):626-635. DOI： 10.11777/j.issn1000-3304.2022.22021.

摘要

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.

Abstract

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 crosslinke

d 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.

关键词

肠道菌群甘草酸甘草次酸P-糖蛋白化疗

Keywords

Gut microbiotaGlycyrrhizinGlycyrrhetinic acidP-gpChemotherapy

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