Oral targeted delivery of Imatinib by pH responsive copolymer modulates liver fibrosis in the mice model

Abstract

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine. Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA). Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity.

Keywords: Imatinib; Liver fibrosis; Targeted nanoparticles; Vitamin A.