一种新葡萄糖偶联物材料TPGS1000-Glu及其修饰的表阿霉素脂质体在治疗脑胶质瘤中的应用

doi:10.5246/jcps.2016.04.030

中国药学(英文版) ›› 2016, Vol. 25 ›› Issue (4): 266-274.DOI: 10.5246/jcps.2016.04.030

一种新葡萄糖偶联物材料TPGS1000-Glu及其修饰的表阿霉素脂质体在治疗脑胶质瘤中的应用

沐黎敏, 吴佳栓, 谢红军, 刘磊, 曾凡, 阎妍, 赵曜, 胡英杰, 卜英子, 吕万良^*

北京大学医学部药学院天然药物与仿生药物国家重点实验室; 分子药剂学与新释药系统北京市重点实验室, 北京 100191

收稿日期:2015-12-16 修回日期:2016-01-15 出版日期:2016-04-21 发布日期:2016-01-25
通讯作者: Tel.: 86-10-82802683, E-mail: luwl@bjmu.edu.cn
基金资助:
National Basic Research Program of China (973 Program, Grant No. 2013CB932501), Beijing Natural Science Foundation (Grant No. 7131009), and National Natural Science Foundation of China (Grant No. 81373343).

The use of a new functional glucose conjugate material, TPGS1000-Glu, in treatment of brain glioma by incorporating into epirubicin liposomes

Limin Mu, Jiashuan Wu, Hongjun Xie, Lei Liu, Fan Zeng, Yan Yan, Yao Zhao, Yingjie Hu, Yingzi Bu, Wanliang Lu^*

Beijing Key Laboratory of Molecular Pharmaceutics and New Drug System; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2015-12-16 Revised:2016-01-15 Online:2016-04-21 Published:2016-01-25
Contact: Tel.: 86-10-82802683, E-mail: luwl@bjmu.edu.cn
Supported by:
National Basic Research Program of China (973 Program, Grant No. 2013CB932501), Beijing Natural Science Foundation (Grant No. 7131009), and National Natural Science Foundation of China (Grant No. 81373343).

摘要/Abstract

摘要：

大多数抗肿瘤药物难以穿透血脑屏障(BBB)因而无法用于脑胶质瘤的治疗。葡萄糖转运体(GLUTs)在血脑屏障和脑胶质瘤细胞上均有高度表达, 这使得葡萄糖转运体相关配体修饰的药物载体跨越血脑屏障、靶向脑胶质瘤细胞成为可能。本研究之目的在于合成一种新的葡萄糖转运体配体靶向材料TPGS₁₀₀₀-Glu、制备TPGS₁₀₀₀-Glu修饰的表阿霉素脂质体,并评价该脂质体制剂的药物效应。评价方法主要在体外血脑屏障共培养模型和脑胶质瘤细胞上进行。TPGS₁₀₀₀-Glu以TPGS₁₀₀₀-COOH和4-氨基苯基-β-D-吡喃葡萄糖苷(Glu)为原料进行合成。基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS)验证结果显示, 试验成功的合成了TPGS₁₀₀₀-Glu。研制的TPGS₁₀₀₀-Glu修饰表阿霉素脂质体具有包封率高(>97%)、纳米粒径(~90nm)、在含血清缓冲体系中药物泄漏少等理化特征。本研究还建立了血脑屏障与脑胶质瘤共培养模型, 在该模型中加入TPGS₁₀₀₀-Glu修饰表阿霉素脂质体后, 该脂质体药物表现出明显的跨越血脑屏障效应、并在跨越血脑屏障后表现出较强的脑胶质瘤细胞摄取效应及抗脑胶质瘤效应。因此, 合成的TPGS₁₀₀₀-Glu为血脑屏障提供了一种新的靶向配体, 而所制备的TPGS₁₀₀₀-Glu修饰表阿霉素脂质体则为脑胶质瘤治疗提供了一种有潜力的抗肿瘤制剂。

关键词: TPGS1000-Glu, 表阿霉素, 脂质体, 葡萄糖转运体, 脑胶质瘤

Abstract:

Most of anticancer agents can not be used for treatment of brain glioma due to the existence of the blood brain barrier (BBB). The over-expression of glucose transporters (GLUTs) on the BBB and brain glioma cells enables the possibility that the GLUTs ligand modified drug carrier transports across the BBB, and targets to the brain glioma cells. The objectives of the present study were to synthesize a new glucose conjugate material, TPGS₁₀₀₀-Glu, develop a kind of TPGS₁₀₀₀-Glu modified epirubicin liposomes, and evaluate their efficacy. The studies were performed on the BBB co-culture model and brain glioma cells in vitro. TPGS1000-Glu was synthesized by conjugating TPGS_1000-COOH with 4-aminophenyl-β-D-glucopyranoside (Glu), and confirmed by MALDI-TOF-MSspectrum. TPGS₁₀₀₀-Glu modified epirubicin liposomes were prepared with a high drug encapsulation efficiency (>97%), a nanosize (approximately 90 nm), and a minimal drug leakage in fetal bovine serum (FBS)-containing buffer system. The BBB co-culture model was established, and after applying TPGS₁₀₀₀-Glu modified epirubicin liposomes to the model, transport of liposomal drug across the BBB was evidenced. Besides, TPGS₁₀₀₀-Glu modified epirubicin liposomes showed the strongest cellular drug uptake and anti-glioma efficacy after transport across the BBB in vitro. The synthesized TPGS1000-Glu material could offer a new targeting ligand for the BBB, while the developed TPGS₁₀₀₀-Glu modified epirubicin liposomes might provide a potential anticancer formulation for treatment of brain glioma.

Key words: TPGS1000-Glu, Epirubicin, Liposomes, Glucose transporters, Brain glioma

中图分类号:

R943

Supporting:

沐黎敏, 吴佳栓, 谢红军, 刘磊, 曾凡, 阎妍, 赵曜, 胡英杰, 卜英子, 吕万良. 一种新葡萄糖偶联物材料TPGS1000-Glu及其修饰的表阿霉素脂质体在治疗脑胶质瘤中的应用[J]. 中国药学(英文版), 2016, 25(4): 266-274.

Limin Mu, Jiashuan Wu, Hongjun Xie, Lei Liu, Fan Zeng, Yan Yan, Yao Zhao, Yingjie Hu, Yingzi Bu, Wanliang Lu. The use of a new functional glucose conjugate material, TPGS1000-Glu, in treatment of brain glioma by incorporating into epirubicin liposomes[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(4): 266-274.

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一种新葡萄糖偶联物材料TPGS1000-Glu及其修饰的表阿霉素脂质体在治疗脑胶质瘤中的应用

The use of a new functional glucose conjugate material, TPGS1000-Glu, in treatment of brain glioma by incorporating into epirubicin liposomes

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