Liver fibrosis results from excessive extracellular matrix accumulation due to injury and leads to
cirrhosis,
cancer, and death. Herein, we propose a
chemokine receptor 4 (CXCR4)-targeted combination (CTC) liposomal
therapy to treat
carbon tetrachloride (CCl4)-induced
liver fibrosis in a mouse model. This study aims to combine small molecules such as
pirfenidone and
AMD3100 in a single nanoplatform to investigate their synergistic antifibrotic effects in a setting of CCl4-induced
liver fibrosis. CTC
liposomes (CTC lipo) were prepared using the thin-film hydration method. CTC lipo exhibited a spherical shape, and the particle size was recorded at the nanoscale which confirms its appropriateness for in vitro and in vivo applications. CTC lipo had good storage and serum stability. The entrapped drugs in CTC lipo showed reduced toxicity at higher concentrations. CTC lipo displayed CXCR4 mediated cell uptake and were internalized by caveolae-mediated endocytosis. CTC lipo showed CXCR4 targeting and stromal cell-derived factor 1α (SDF1-α)/CXCR4 axis blocking activity. CTC lipo reduced the elevated serum
aspartate aminotransferase (AST),
alanine transaminase (ALT), and
hydroxyproline (HYP) levels. The histological studies showed improved liver architecture and reduced
collagen deposition
after treatment.
Transforming growth factor β (TGFβ), alpha-smooth muscle actin (α-SMA), and
collagen I were elevated by CCl4 in comparison with the
Sham. Upon CTC liposomal treatment, the quantitative score for the elevated fibrotic
proteins such as TGFβ, α-SMA, and
collagen I was normalized. CTC lipo displayed significant downregulation of the upregulated TGFβ, α-SMA,
collagen I, and P-p38 expressions at the molecular level. The CXCR4 targeted
liposomes showed prolonged biodistribution at 24 h. Our findings indicated that CTC lipo might be an alternative antifibrotic
therapy that may offer new access to research and development. In a nutshell, the present study suggests that systemic administration of CTC lipo has efficient antifibrotic potential and deserves to be investigated for further clinical applications.