Angiopep-2 and Activatable Cell-Penetrating Peptide Dual-Functionalized Nanoparticles for Systemic Glioma-Targeting Delivery
Angiopep-2 and Activatable Cell-Penetrating Peptide Dual-Functionalized Nanoparticles for Systemic Glioma-Targeting Delivery
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DOI：
10.1021/mp500113p
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发表时间：
2014-08-01
影响因子：
4.9
通讯作者：
Jiang, Xinguo
中科院分区：
文献类型：
--
作者：
Gao, Huile;Zhang, Shuang;Jiang, Xinguo
胶质瘤很难治疗，因为它涉及两种屏障：血脑屏障和血肿瘤屏障。在这项研究中，一种双靶向配体angiopep-2和一种可激活的细胞穿透肽（ACP）被功能化到纳米颗粒上，用于胶质瘤靶向递送。ACP通过基质金属蛋白酶-2 （MMP-2）敏感连接体将RRRRRRRR （R8）与EEEEEEEE偶联而成。由于MMP-2在C6细胞上的高表达，ACP修饰有效地增强了C6细胞的摄取。MMP-2抑制剂batimastat抑制了ACP的摄取，表明MMP-2激活了ACP的细胞穿透特性。通过结合angiopep-2的双靶向递送作用和ACP的可激活细胞穿透特性，双修饰纳米颗粒（AnACNPs）比单配体修饰纳米颗粒具有更高的胶质瘤定位能力。在多西他赛（一种常见的化疗药物）的负荷下，AnACNPs在体外和体内都显示出最有利的抗胶质瘤作用。因此，我们开发了一种新的胶质瘤双靶向穿透给药系统。结果表明，该系统有效靶向胶质瘤，提供了最有利的抗胶质瘤效果。
Gliomas are hard to treat because of the two barriers involved: the blood brain barrier and blood tumor barrier. In this study, a dual-targeting ligand, angiopep-2, and an activatable cell-penetrating peptide (ACP) were functionalized onto nanoparticles for glioma-targeting delivery. The ACP was constructed by conjugating RRRRRRRR (R8) with EEEEEEEE through a matrix metalloproteinase-2 (MMP-2)-sensitive linker. ACP modification effectively enhanced the C6 cellular uptake because of the high expression of MMP-2 on C6 cells. The uptake was inhibited by batimastat, an MMP-2 inhibitor, suggesting that the cell-penetrating property of the ACP was activated by MMIP-2. By combining the dual-targeting delivery effect of angiopep-2 and activatable cell-penetrating property of the ACP, the dual-modified nanoparticles (AnACNPs) displayed higher glioma localization than that of single ligand-modified nanoparticles. After loading with docetaxel, a common chemotherapeutic, AnACNPs showed the most favorable antiglioma effect both in vitro and in vivo. In conclusion, a novel drug delivery system was developed for glioma dual targeting and glioma penetrating. The results demonstrated that the system effectively targeted gliomas and provided the most favorable antiglioma effect.