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

Ryohei Miyata, Masakazu Ueda, Hiromitsu Jinno, Tomohiro Konno, Kazuhiko Ishihara, Nobutoshi Ando, Yuko Kitagawa

研究成果: Article査読

24 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2460-2467
ページ数8
ジャーナルInternational Journal of Cancer
124
10
DOI
出版ステータスPublished - 2009 5 15
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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