Long-Circulating Liposomal Delivery System Targeting at PDGFR-β Enhances the Therapeutic Effect of IFN-α on Hepatic Fibrosis

Background: In this study, we developed a drug of IFN-alpha combined with pPB-SSLs, which specifically target at platelet-derived growth factor receptor-beta (PDGFR-beta). Aim: The aim of this study is to improve the limitations of IFN-alpha including insufficient drug concentration for the target cells and side-effects causing serious concerns in treatment of hepatic fibrosis. Methods: We constructed the targeted stable liposomes (SSLs) that not only increase the half-life period of IFN-alpha, but also can deliver IFN-alpha to hepatic stellate cells (HSCs). Subsequently, the anti-hepatic-fibrosis effect of pPB-SSL-IFN-alpha was evaluated both in vitro and in vivo. Immunofluorescent assay showed that the pPB-SSL particles were able to be easily taken up by 3T3 cells. The cellular distribution experiment demonstrated that most of the pPB-SSL-IFN-alpha would accumulate around the fibroblast, and the cell would be invaded by pPB-SSL-IFN-alpha. Results: The pPB-SSL-IFN-alpha showed an entrapment efficiency of 39.73 +/- 5.21% for IFN-alpha and the particles reached nanoscale level. It showed more significant alleviated performance for hepatic fibrosis than IFN-alpha. Both in vitro and in vivo, the pPB-SSL-IFN-alpha could contribute to reduction or inhibition in the expression of TGF-beta 1 and alpha-SMA even cleavage of caspase-3. Moreover, it was found that the pPB-SSL-IFN-alpha induced the apoptosis of 3T3 cells by inhibiting the expression of TGF-beta 1 as well as alpha-SMA. Under observation for fibrotic liver of mice treated with pPB-SSL-IFN-alpha, the semiquantitative score for collagen I, TGF-beta 1 and alpha-SMA were all inferior to the control group and those treated with PEG-IFN-alpha, SSL-IFN-alpha or IFN-alpha. In addition, pPB-SSL-IFN-alpha has been detected to down-regulate the expression of TNF-alpha and IL-1 beta in comparison with model group (P<0.01). And the phosphorylations of JAK1 and STAT1 were enhanced by pPB-SSL-IFN-alpha in comparison with model groups (P < 0.01). Conclusion: All results of our present research indicated that the pPB-SSL-IFN-alpha might be an alternative anti-liver fibrotic drug and the synthetic method may offer a new access to the anti-hepatic fibrosis research and development.