肝星状细胞
硫酸软骨素
CD44细胞
肝细胞学
高尔基体
细胞生物学
细胞外基质
透明质酸
内化
化学
去唾液酸糖蛋白受体
体内
肝纤维化
癌症研究
纤维化
肝细胞
糖胺聚糖
医学
生物
生物化学
受体
病理
细胞
体外
肝脏代谢
作者
Jingwen Luo,Pei Zhang,Ting Zhao,Mengdi Jia,Peng Yin,Wenhao Li,Zhirong Zhang,Yao Fu,Tao Gong
出处
期刊:ACS Nano
[American Chemical Society]
日期:2019-04-02
卷期号:13 (4): 3910-3923
被引量:56
标识
DOI:10.1021/acsnano.8b06924
摘要
Liver fibrosis is a serious liver disease associated with high morbidity and mortality. The activation of hepatic stellate cells (HSCs) and the overproduction of extracellular matrix proteins are key features during disease progression. In this work, chondroitin sulfate nanomicelles (CSmicelles) were developed as a delivery system targeting HSCs for the treatment of liver fibrosis. CS-deoxycholic acid conjugates (CS-DOCA) were synthesized via amide bond formation. Next, retinoic acid (RA) and doxorubicin (DOX) were encapsulated into CSmicells to afford a DOX+RA-CSmicelles codelivery system. CSmicelles were selectively taken up in activated HSCs and hepatoma (HepG2) cells other than in normal hepatocytes (LO2), the internalization of which was proven to be mediated by CD44 receptors. Interestingly, DOX+RA-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. Following tail-vein injection, DOX+RA-CSmicelles were delivered to the cirrhotic liver and showed synergistic antifibrosis effects in the CCl4-induced fibrotic rat model. Further, immunofluorescence staining of dissected liver tissues revealed CD44-specific delivery of CS derivatives to activated HSCs. Together, our results demonstrate the great potential of CS based carrier systems for the targeted treatment of chronic liver diseases.
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