Targeted truncated TGF-β receptor type II delivery to fibrotic liver by PDGFβ receptor-binding peptide modification for improving the anti-fibrotic activity against hepatic fibrosis in vitro and in vivo.

Truncated transforming growth factor-β receptor type II (tTβRII) is a promising anti-fibrotic candidate because it attenuates excessive transforming growth factor-β1 (TGF-β1) and then blocks TGF-β1 activity in hepatic fibrosis. However, its use has been greatly limited due to the fact that it is expensive to chemically synthesize and it does not specifically target to the lesion site. In this study, we describe that platelet-derived growth factor β receptor (PDGFβR)-binding peptide BiPPB modified tTβRII (BiPPB-tTβRII) was prepared from the cleavage of SUMO-BiPPB-tTβRII by digestion with SUMO-specific protease. Moreover, compared to the unmodified tTβRII, the target protein BiPPB-tTβRII not only highly specific targeted activated hepatic stellate cells (HSCs) and fibrotic liver tissue, but also significantly inhibited the protein levels of fibrosis-related genes in TGF-β1-induced HSC-T6 cells and CCl4-induced liver fibrosis in mice. Furthermore, BiPPB-tTβRII markedly ameliorated liver morphology, fibrotic responses and the damage of liver function in fibrosis animal. More importantly, BiPPB-tTβRII showed a much lesser extent in binding to quiescent HSCs and non-fibrotic liver tissue. Taken together, our results suggested that the target protein BiPPB-tTβRII, with its high specific fibrotic liver-targeting potential and its improved anti-fibrotic activity in liver fibrosis, may be a potential therapeutic agent for liver fibrosis.