Theranostics 2018; 8(4):894-905. doi:10.7150/thno.21168
Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development
1. Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
2. Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan
3. Department of Biostatistics, University of North Caroline at Chapel Hill
4. Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin Chu City 30059, Taiwan
5. Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
6. Institute of Atomic and Molecular Sciences (IAMS), Academia Sinica, National Taiwan University, Taipei, Taiwan
7. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
† These authors contributed equally to this work.
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.
Keywords: CXCR4-targeted nanoparticle, MAPK/ERK pathway, liver fibrosis, hepatocellular carcinoma, liver metastasis
Sung YC, Liu YC, Chao PH, Chang CC, Jin PR, Lin TT, Lin JA, Cheng HT, Wang J, Lai CP, Chen LH, Wu AY, Ho TL, Chiang T, Gao DY, Duda DG, Chen Y. Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development. Theranostics 2018; 8(4):894-905. doi:10.7150/thno.21168. Available from http://www.thno.org/v08p0894.htm