A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas
A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas
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基于与转铁蛋白和他莫昔芬缀合的聚（酰胺基胺）树状聚合物的双靶向纳米载体用于治疗脑胶质瘤
DOI：
10.1016/j.biomaterials.2012.02.004
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发表时间：
2012-05-01
期刊：
影响因子：
14
通讯作者：
Wei, Yen
中科院分区：
文献类型：
--
作者：
Li, Yan;He, Hai;Wei, Yen
以转铁蛋白（TO）和他莫昔芬（TAM）为骨架，合成了一种pH敏感的双靶向药物载体（G4-DOX-PEG-Tf-TAM），用于增强血脑屏障（BBB）的转运和药物在胶质瘤细胞内的蓄积。结果表明，平均每个G4 PAMAM树枝状大分子的外围有7个阿霉素（DOX）分子，30多个PEG（1000）和PEG（2000）链以及1个Tf基团，而每个树枝状大分子的内部有29个TAM分子。在pH 4.5和pH 7.4条件下，DOX的释放率分别为32%和6%，表明在弱酸性条件下药物释放较快，载体在生理环境下稳定。体外血脑屏障模型药物转运实验表明，G4-DOX-PEG-Tf-TAM具有较强的血脑屏障转运能力，3 h转运率为6.06%。通过转铁蛋白受体介导的内吞作用和三苯氧胺对药物外排转运的抑制作用，该载体在穿过血脑屏障模型时被内化到C6胶质瘤细胞中。此外，还显示DOX在无血管的C6胶质瘤球体中的体外蓄积使肿瘤体积有效缩小。(C)2012爱思唯尔有限公司保留所有权利。
A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (TO conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG(1000) and PEG(2000) chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced. (C) 2012 Elsevier Ltd. All rights reserved.