title: Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.
abstract: The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine , Taoyuan, Taiwan, R.O.C.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Chan
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Tsaiyu
authors.initials: T
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Guann-Gen
authors.initials: GG
authors.lastname: Chern
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei, Taiwan, R.O.C.
authors.forename: Fu-Fei
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine , Taoyuan, Taiwan, R.O.C.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University , Hsinchu 30013, Taiwan, R.O.C.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001596:Benzylamines; D002251:Carbon Tetrachloride / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D000080027:Cyclams; D004195:Disease Models, Animal; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D053758:Nanoparticles / Q000008:administration & dosage*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D002251:Carbon Tetrachloride; C088327:plerixafor
keywords: CXCR4/SDF-1α; VEGF; angiogenesis; liver fibrosis; nanoparticle; siRNA delivery