Enzymatic synthesis of three kinds of galactose-cholesterol ligands and their structure-activity relationship with liver targeting / 中草药

ABSTRACT

Objective To construct three kinds of doxorubicin liposomes modified with cholesterol-galactose ligand by lipase-catalyzed method and compare their characteristic of pharmacokinetics and tissue distribution in vivo. Methods Three types of cholesterol-galactose ligands, CHS-C8-GalNAc, CHS-C8-GAL, and CHS-C8-LA were synthetized by lipase-catalyzed method in nonaqueous phase. The structure characterizations of products were obtained by MS and NMR. Conventional liposomes (CL DOX) and ligand-coupled liposomes (NGal-LP DOX, Gal-LP DOX, and LA-LP DOX) were prepared by thin film dispersion-ammonium sulphate gradient method. Structure-activity relationship between asialoglycoprotein receptor (ASGPr) and the chemical structure of the glycolipids was explored through the pharmacokinetics and tissue distribution parameters of ligand-coupled liposomes in vivo. Results The desired compounds with a high yield of above 90% were confirmed by MS and NMR. The liposomes average size was lower than 90 nm, polymer dispersity index was lower than 0.1, encapsulation efficiency was greater than 99%, leakage rat was lower than 5% with 24 h, and zeta potential closed to zero. The affinity of the three ligand molecules to liver was the following order: CHS-C8-GalNAc > CHS-C8-LA > CHS-C8-Gal. However, only the liposomes modified with CHS-C8-GalNAc could significantly be inhibited by the preinjection of asialofetuin for hepatic uptake rate (P 0.05). Conclusion The ligand with N-acetylgalactosamine residue showed high targeting efficiency for hepatocytes, while the ligand with D-galactose (Gal) or lactitol residue could competitive bind with Gal particle receptor on kupffer cells.