Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide
Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide
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通过稳定的糖肽实现基于纳米盘的神经胶质瘤靶向药物递送
DOI：
10.1016/j.jconrel.2018.06.006
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发表时间：
2018
影响因子：
10.8
通讯作者：
Wang Hao
中科院分区：
文献类型：
--
作者：
Wang Huan;Wang Xiaoyi;Xie Cao;Zhang Mingfei;Ruan Huitong;Wang Songli;Jiang Kuan;Wang Fei;Zhan Changyou;Lu Weiyue;Wang Hao
七肽 ATWLPPR (A7R) 与神经胶质瘤细胞中过表达的血管内皮生长因子受体 2 (VEGFR2) 和神经毡蛋白-1 (NRP-1) 特异性结合，具有实现神经胶质瘤靶向药物递送的巨大潜力。然而，由于A7R蛋白水解稳定性差且难以进入大脑，A7R肽的体内应用仍然具有挑战性。为了解决这些问题，我们鉴定了一种糖基化 A7R 衍生物来增强体内稳定性和脑转运功效。我们的结果表明，肽的糖基化可以有效提高血清稳定性，穿过血脑屏障（BBB）并被神经胶质瘤细胞摄取。此外，以糖肽为靶向部分、纳米盘为紫杉醇（PTX）载体，成功构建了一种新型胶质瘤靶向药物递送系统。物理化学表征表明，纳米盘具有合适的50nm尺寸和足够的PTX负载能力。与非糖基化纳米盘相比，糖肽修饰可以显着增强脑毛细血管内皮细胞通过葡萄糖转运蛋白1（GLUT1）对纳米盘的摄取。体内成像和胶质瘤荧光切片结果也表明，糖肽修饰的纳米盘在胶质瘤中表现出更高的积累。糖肽驱动的 PTX 递送系统在颅内神经胶质瘤异种移植模型中表现出优异的抗神经胶质瘤功效。这些结果表明肽的糖基化为设计多功能且稳定的脑靶向配体提供了有效的途径。
Heptapeptide ATWLPPR (A7R) binds specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However,in vivoapplication of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhancein vivostability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier (BBB) and be uptaken by glioma cells. Furthermore, a novel glioma-targeted drug delivery system was constructed successfully employing glycopeptide as the targeting moiety and nanodisk as the carrier of paclitaxel (PTX). Physicochemical characterization showed that the nanodisk presented suitable size of 50 nm and adequate loading capacity of PTX. Compared to non-glycosylated nanodisk, glycopeptide modification could significantly enhance the uptake of disks by brain capillary endothelial cells through glucose transporter 1 (GLUT1).In vivoimaging and glioma fluorescence section results also indicated that nanodisks modified with glycopeptide showed a higher accumulation in glioma. The glycopeptide-enabled PTX delivery system exhibited superior anti-glioma efficacy in intracranial glioma xenograft model. These results suggested that glycosylation of peptides provided an efficient pathway to design multifunctional and stable brain targeting ligands.