Liver fibrosis is induced by chronic liver inflammation and leads to liver cancer. Recently, delivery of matrix metalloprotease (MMP) or its transcription factor to hepatocytes has been developed as a new treatment approach for liver fibrosis. MMP can degrade collagen in fibrotic tissues and is expected to improve liver fibrosis. To realize this novel treatment for liver fibrosis, the development of delivery carriers that can specifically deliver MMP or its transcription factors to hepatocytes is required.<br/>Hepatocytes have asialoglycoprotein receptors (ASGR) on their surface, which selectively recognize sugar-moieties such as galactose. In addition, transcription factor should be introduced to cytosol of hepatocytes by escaping from endo/lysosomal degradation. In this study, we designed polyamidoamine dendron-bearing lipids with galactose moieties (Gal-DL) as a targeting ligand to hepatocytes. Furthermore, pH-sensitive polymer-lipid, 2-carboxycyclohexane-1-carboxylated poly(glycidol)-modified distearoyl phosphatidylethanolamine (CHexPG-PE) was used to promote endosomal escape of carrier. Liposomes modified with both Gal-DL and CHexPG-PE are expected to be recognized by ASGR and accumulate to the liver tissue. After internalization to hepatocytes, CHexPG-PE becomes hydrophobic in response to low pH of endosome and destabilizes endosomal membrane, which might lead to cytosol release of MMP transcription factors. Here, the synthesis of Gal-DL, characterization of Gal-DL/CHexPG-PE-modified liposomes and interaction of these liposomes with hepatocytes were examined.

Liver-specific DDS using liposomes modified with sugar moiety-introduced dendron lipids and pH-responsive polymer-lipids

255th National Meeting (2018)

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