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
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
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DOI：
10.1002/ijc.24227
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发表时间：
2009-05
影响因子：
6.4
通讯作者：
Ryohei Miyata;M. Ueda;H. Jinno;T. Konno;K. Ishihara;N. Ando;Y. Kitagawa
中科院分区：
文献类型：
--
作者：
Ryohei Miyata;M. Ueda;H. Jinno;T. Konno;K. Ishihara;N. Ando;Y. Kitagawa
以二硫代酯封端的2-甲基丙烯酰氧乙基磷酰胆碱（MPC）为大分子链转移剂，合成了以甲基丙烯酸正丁酯（BMA）为疏水成核嵌段的二嵌段共聚物。MPC-BMA单元与可固定单元甲基丙烯酸对硝基苯基羰基氧基乙酯（NPMA）共聚。然后通过添加B型肝炎表面抗原（HBsAg）的preS 1结构域来修饰NPMA部分。这种胶束形成纳米颗粒，即与preS 1缀合的聚（MPC-co-BMA-co-NPMA）（PMBN），能够使紫杉醇（PTX）增溶，并增加肝向性。PTX和PTX/PMBN-preS 1对人肝癌细胞系HepG 2的50%抑制浓度（IC 50）值分别为1，008和131 nM（p < 0.05）。结合前S1 PMBN强烈增强协同抑制作用的紫杉醇对HepG 2细胞在体外，而这种变化的IC 50没有检测到对人类鳞状细胞癌细胞系，A431。Balb/c裸鼠腹腔注射PTX、PTX/PMBN和PTX/PMBN-preS 1后，HepG 2异种移植物的肿瘤生长率分别为+97.9%、-74.3%和-96.2%*（*p < 0.05 vs PTX）。通过高效液相色谱法测定异种移植物中PMBN-preS 1偶联物给药后的局部紫杉醇水平，其比紫杉醇单独给药后高8倍。在重要器官中未观察到可归因于PMBN-preS 1的组织学副作用，PTX/PMBN-preS 1组的体重减轻显著较少。这些研究表明，PMBN-preS 1可用作人肝细胞特异性药物递送载体，无严重不良反应。© 2008 Wiley利斯公司
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.