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.

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

“…CXCR4 is a chemokine receptor induced in activated HSCs by various cellular stresses during the progression of liver fibrosis 16 , 26 , 27 . Thus, we developed CXCR4-targeted NPs to more selectively target activated HSCs in fibrotic livers 27 . In this study, to improve safety and efficacy of the drug cocktail, we co-formulated sorafenib and AZD6244 in CXCR4-targeted lipid-coated PLGA NPs modified with CTCE9908, a CXCR4 antagonist peptide.…”

Kaempferol attenuates liver fibrosis by inhibiting activin receptor–like kinase 5

“…As the ATP‐binding pocket is the core structure of the catalytic domain of ALK5, this interaction could, at least partially, explain the down‐regulation of TGF‐β1/Smad2/3 signalling after kaempferol intervention. Similarly, small interfering RNAs (siRNAs) could also target specific proteins such as VEGF, MMP‐2 and Foxf1 to attenuate extracellular matrix deposition and liver fibrosis formation. However, how to delivery siRNAs into targeted cells effectively and efficiently remains to be a problem that needs to be solved .…”

Recent Advances in Nanomedicine for the Diagnosis and Therapy of Liver Fibrosis

“…A study used pPB-modified liposomes to deliver recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) to the HSC membrane, prolonging rhTRAIL circulation in vivo and alleviating fibrosis both in vitro and in vivo [ 90 ]. Similarly, the CXCR4 antagonist AMD3100 could target HSCs [ 91 ]. AMD3100-conjugated liposomes efficiently delivered therapeutic VEGF siRNAs to activate CXCR4-overexpressed HSCs both in vitro and in vivo.…”