https://scholars.lib.ntu.edu.tw/handle/123456789/552853
標題: | Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development | 作者: | Yun-Chieh Sung Ya-Chi Liu Po-Han Chao Chih-Chun Chang Pei-Ru Jin Ts-Ting Lin Ja-An Lin HUI-TENG CHENG Jane Wang Charles P. Lai Ling-Hsuan Chen Anthony Y. Wu Ting-Lun Ho Tsaiyu Chiang Dong-Yu Gao Dan G. Duda Yunching Chen |
公開日期: | 2018 | 出版社: | Ivyspring International Publisher | 卷: | 8 | 期: | 4 | 起(迄)頁: | 894-905 | 來源出版物: | Theranostics | 摘要: | Liver damage and fibrosis are precursors of hepatocellular carcinoma (HCC). In HCC patients, sorafenib-a multikinase inhibitor drug-has been reported to exert anti-fibrotic activity. However, incomplete inhibition of RAF activity by sorafenib may also induce paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in malignant cells. The consequence of this effect in non-malignant disease (hepatic fibrosis) remains unknown. This study aimed to examine the effects of sorafenib on activated hepatic stellate cells (HSCs), and develop effective therapeutic approaches to treat liver fibrosis and prevent cancer development. Methods: We first examined the effects of sorafenib in combination with MEK inhibitors on fibrosis pathogenesis in vitro and in vivo. To improve the bioavailability and absorption by activated HSCs, we developed CXCR4-targeted nanoparticles (NPs) to co-deliver sorafenib and a MEK inhibitor to mice with liver damage. Results: We found that sorafenib induced MAPK activation in HSCs, and promoted their myofibroblast differentiation. Combining sorafenib with a MEK inhibitor suppressed both paradoxical MAPK activation and HSC activation in vitro, and alleviated liver fibrosis in a CCl4-induced murine model of liver damage. Furthermore, treatment with sorafenib/MEK inhibitor-loaded CXCR4-targeted NPs significantly suppressed hepatic fibrosis progression and further prevented fibrosis-associated HCC development and liver metastasis. Conclusions: Our results show that combined delivery of sorafenib and a MEK inhibitor via CXCR4-targeted NPs can prevent activation of ERK in activated HSCs and has anti-fibrotic effects in the CCl4-induced murine model. Targeting HSCs represents a promising strategy to prevent the development and progression of fibrosis-associated HCC. ? Ivyspring International Publisher. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85040005273&doi=10.7150%2fthno.21168&partnerID=40&md5=408a4652cfc545b6f9a8e0fd2d21fb2d https://scholars.lib.ntu.edu.tw/handle/123456789/552853 |
ISSN: | 1838-7640 | DOI: | 10.7150/thno.21168 | SDG/關鍵字: | chemokine receptor CXCR4; mitogen activated protein kinase; mitogen activated protein kinase kinase inhibitor; nanoparticle; selumetinib; sorafenib; chemokine receptor CXCR4; chloroform; CXCR4 protein, mouse; nanoparticle; protein kinase inhibitor; sorafenib; animal experiment; animal model; animal tissue; antifibrotic activity; Article; cancer prevention; cell activation; cell differentiation; cell survival; cell viability; controlled study; drug activity; drug effect; drug mechanism; enzyme activation; hepatic stellate cell; in vitro study; in vivo study; liver carcinogenesis; liver cell carcinoma; liver fibrosis; liver injury; liver metastasis; male; mouse; myofibroblast; nonhuman; tumor volume; animal; antagonists and inhibitors; chemically induced; disease model; liver cell carcinoma; liver cirrhosis; liver tumor; metabolism; physiology; treatment outcome; Animals; Carcinoma, Hepatocellular; Chloroform; Disease Models, Animal; Hepatic Stellate Cells; Liver Cirrhosis; Liver Neoplasms; Mice; Nanoparticles; Protein Kinase Inhibitors; Receptors, CXCR4; Sorafenib; Treatment Outcome |
顯示於: | 醫學系 |
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