A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas

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• 作者：Yan Li^a ; Hai He^a ; Xinru Jia^a ; ^{xrjia@pku.edu.cn} ; Wan-Liang Lu^b ; ; Jinning Lou^c ; Yen Wei^d
• 关键词：Blood-brain barrier (BBB) ; PAMAM ; Dual-targeting ; pH-sensitive ; Gliomas
• 刊名：Biomaterials
• 出版年：2012
• 期刊代码：7_01429612
• 类别：ms
• 出版时间：May, 2012
• 卷：33
• 期：15
• 页码：3899-3908
• 文件大小：1610 K

摘要

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) 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 PEG₁₀₀₀ and PEG₂₀₀₀ 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聽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聽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聽vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced.