Figure 4.

Sorafenib and the MEK inhibitor AZD6244 co-formulated in CTCE9908-NPs decrease liver fibrosis and suppress angiogenesis in the CCl₄-induced mouse model of liver fibrosis. A, Treatment schedule of sorafenib and AZD6244 loaded in different formulations in the CCl₄-induced murine model of liver damage. B, Western blot analysis showed co-delivery of sorafenib and AZD6244 suppressed ERK activation induced by sorafenib in the fibrotic livers of CCl₄-treated mice. C, Sorafenib and AZD6244 loaded in CXCR4-targeted NPs inhibited mRNA expression of inflammatory and fibrotic markers such as TNF-α, IL-1b, IL-6, ACTA2, PPARγ, Col1A1 (normalized by β-actin). D, Sorafenib and AZD6244 delivered by CTCE9908-NPs (5 mg/kg, I.V., two doses per week) significantly ameliorated liver fibrosis in CCl₄-treated mice, as indicated by Masson's trichrome and IF staining for collagen I, α-SMA and von Willebrand factor (vWF) (scale bar=100 μm) (n=5-15). E-F, Quantification of collagen I (E) and α-SMA (F) expression in randomly selected fields within the fibrotic livers (n=9-16). G, Sorafenib and AZD6244 loaded in different formulations reduced liver fibrosis in a dose-dependent manner, as indicated by a decrease in collagen I deposition in the fibrotic livers (n=5-16). The data are presented as mean values ± S.E.M., **p<0.01 and ***p<0.001.