Self-assembled drug delivery systems. Part 7: hepatocyte-targeted nanoassemblies of an adefovir lipid derivative with cytochrome P450-triggered drug release.

A novel strategy was used in the design of self-assembled drug delivery systems (SADDSs) in this study. The nanoassemblies of an amphiphilic adefovir lipid derivative were prepared and demonstrated to have the functions of hepatocyte targeting, enzyme-triggered drug release and high anti-hepatitis effect. An amphiphilic adefovir lipid derivative, N-lauroyl-1-(3-chlorophenyl)-1,3-propanyl phosphonyl adefovir (LCPA) was prepared and formed the nanoassemblies by injecting the mixture of LCPA and another amphiphilic polymer, d-galactide polyoxyethylene (20) cetyl ether (GPCE) (ca. 20:1, mol/mol) into water. The nanoassemblies were very stable and showed negative charge. LCPA was sensitive to the cytochrome P450 isozymes that were expressed predominantly in the hepatocytes to produce adefovir. GPCE contained a long hydrophilic chain and a galactose ligand targeting the asialoglycoprotein receptors overexpressed on the surface of hepatocytes. The nanoassemblies showed the long-circulating and liver targeting effects according to the results of pharmacokinetics, tissue distribution and fluorescence imagination after bolus intravenous administration of the nanoassemblies to the mice. The highly efficient hepatitis B treatment was achieved by 10 day continuous administration of the nanoassemblies to the HBV-infected mice. Many functions were combined in the nanoassemblies, including prodrug, molecular self-assembly, nanotechnology, long-circulating, hepatocyte targeting and hepatocyte over expressing enzyme-triggered drug release.