Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development
Journal
Theranostics
Journal Volume
8
Journal Issue
4
Pages
894-905
Date Issued
2018
Author(s)
Yun-Chieh Sung
Ya-Chi Liu
Po-Han Chao
Chih-Chun Chang
Pei-Ru Jin
Ts-Ting Lin
Ja-An Lin
Jane Wang
Charles P. Lai
Ling-Hsuan Chen
Anthony Y. Wu
Ting-Lun Ho
Tsaiyu Chiang
Dong-Yu Gao
Dan G. Duda
Yunching Chen
Abstract
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.
SDGs
Other Subjects
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
Publisher
Ivyspring International Publisher
Type
journal article