Polymeric nanoparticles for liver-targeted pituitary tumor-transforming gene 1 silencing in rats with chronic liver disease

Abstract

Pituitary tumor transforming gene 1 (Pttg1) is upregulated in cirrhosis and hepatocarcinoma (HCC). We assessed the therapeutic effect of liver-targeted Pttg1 siRNA Retinol (Ret) pBAE nanoparticles (NPs) to treat these disturbances. Fibrosis was induced in Wistar rats by carbon tetrachloride inhalation and HCC by diethylnitrosamine injection. Ret pBAE NPs accumulated in hepatic tissue, close to zones positive for αSMA staining. Pttg1 interference increased mean arterial pressure, reduced portal hypertension and decreased collagen accumulation and inflammatory infiltrate in fibrotic rats. In HCC rats, Pttg1 silencing reduced liver to body weight ratio and hepatic proliferation and increased hepatic ATP production and serum glucose. This therapy effectively mitigated liver fibrosis and HCC progression in experimental models. The feasibility of this treatment was also demonstrated in human derived hepatic stellate cells and in ex vivo human cirrhotic livers underscoring the therapeutic potential of Pttg1 siRNA Ret pBAE NPs in addressing liver fibrosis and HCC.