Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible,drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Using dithioester‐capped 2‐methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n‐butyl methacrylate (BMA) as hydrophobic core‐forming blocks. The MPC–BMA unit was copolymerized with an immobilizable unit, p‐nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle‐forming nanoparticle, the poly (MPC‐co‐BMA‐co‐NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC₅₀) values of PTX and PTX/PMBN‐preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC₅₀ was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN‐preS1 were +97.9%, ?74.3% and ?96.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN‐preS1 conjugate were determined in the xenografts by high‐performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN‐preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN‐preS1 group. These studies demonstrate that PMBN‐preS1 may be used as a human hepatocyte‐specific drug delivery carrier without serious adverse effects. © 2008 Wiley‐Liss, Inc.