A specific drug targeting system based on polyhydroxyalkanoate granule binding protein PhaP fused with targeted cell ligands
A specific drug targeting system based on polyhydroxyalkanoate granule binding protein PhaP fused with targeted cell ligands
复制标题
基于聚羟基脂肪酸酯颗粒结合蛋白 PhaP 与靶向细胞配体融合的特异性药物靶向系统
DOI：
10.1016/j.biomaterials.2008.09.008
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发表时间：
2008-12-01
期刊：
影响因子：
14
通讯作者：
Chen, Guo-Qiang
中科院分区：
文献类型：
--
作者：
Yao, Yong-Chao;Zhan, Xiao-Yong;Chen, Guo-Qiang
聚羟基烷酸酯(PHA)是一类由多种细菌产生的胞内生物多酯家族。PHA颗粒结合蛋白Phap能够通过强烈的疏水相互作用与疏水聚合物结合。本研究在Phap的基础上开发了一种受体介导的药物传递系统。该体系由PHA纳米颗粒、Phap和与Phap融合的多肽或蛋白质配体组成。PHA纳米颗粒主要用于包装疏水药物；PhaP与其相应基因在毕赤酵母中过表达产生的配体融合，或E.colt能够附着在疏水的PHA纳米颗粒上。最后，配体能够通过配体识别的受体将Phap-PHA纳米颗粒拉到目标细胞上。本研究发现，以甘露糖化人α1-酸性糖蛋白(HAGP)和人表皮生长因子(HEGF)为配体的受体介导的药物递送系统L igand-Phap-PHA纳米粒分别被巨噬细胞、肝癌细胞BEL7402体外摄取，并与巨噬细胞和肝癌细胞的受体结合。以罗丹明B异硫氰酸酯(RBITC)为给药模型药物时，由于特定的配体和受体结合产生的特异性靶向效应，荧光显微镜下可在靶细胞和靶器官(肝脏或肿瘤)中清楚地看到纳米粒子系统。携带RBITC的hEGF-Phap纳米粒的递送系统被肿瘤模型小鼠的肿瘤细胞内吞。因此，配体-Phap-PHA特异性给药系统在体外和体内都被证明是有效的。(C)2008爱思唯尔有限公司。保留所有权利。
Polyhydroxyalkanoates (PHA) is a family of intracellular biopolyesters produced by many bacteria. PHA granule binding protein PhaP is able to bind to hydrophobic polymers via strong hydrophobic interaction. A receptor-mediated drug delivery system was developed in this study based on PhaP. The system consists of PHA nanoparticles, PhaP and polypeptide or protein ligands fused to PhaP. The PHA nanciparticles were used to package mostly hydrophobic drugs; PhaP fused with ligands produced by over-expression of their corresponding genes in Pichia pastoris, or E. colt was able to attach to hydrophobic PHA nanoparticle. At the end, the ligands were able to pull the PhaP-PHA nanoparticles to the targeted cells with receptors recognized by the ligands. It was found in this study that the receptor-mediated drug specific delivery system ligand-PhaP-PHA nanoparticles were taken up by macrophages, hepatocellular carcinoma cell BEL7402 in vitro and liver, hepatocellular carcinoma cells in vivo, respectively, when the ligands were mannosylated human alpha 1-acid glycoprotein (hAGP) and human epidermal growth factor (hEGF), respectively, which were able to bind to receptors of macrophages or hepatocellular carcinoma cells. The nanoparticle system was clearly visible in the targeted cells and organs (liver or tumor) under fluorescence microscopy when rhodamine B isothiocyanate (RBITC) was used as a delivery model drug due to the specific targeting effect created by specific ligand and receptor binding. The delivery system of hEGF-PhaP-nanoparticles carrying RBITC was found to be endocytosed by the tumor cells in tumorous model mice. Thus, the ligand-PhaP-PHA specific drug delivery system was proven effective both in vitro and in vivo. (c) 2008 Elsevier Ltd. All rights reserved.