PEG-co-PCL nanoparticles modified with MMP-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy
PEG-co-PCL nanoparticles modified with MMP-2/9 activatable low molecular weight protamine for enhanced targeted glioblastoma therapy
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用 MMP-2/9 可激活的低分子量鱼精蛋白修饰的 PEG-co-PCL 纳米颗粒用于增强靶向胶质母细胞瘤治疗
DOI：
10.1016/j.biomaterials.2012.09.044
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发表时间：
2013-01-01
期刊：
影响因子：
14
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Gu, Guangzhi;Xia, Huimin;Chen, Jun
利用基质金属蛋白酶MMP-2和MMP-9在胶质母细胞瘤中的表达显著上调以及低分子量鱼精蛋白（LMWP）的强大转运能力，我们构建了可活化的低分子量鱼精蛋白（ALMWP），并将其与PEG-PCL纳米颗粒（NP）偶联，以开发一种“智能”药物递送系统，用于增强胶质母细胞瘤的靶向治疗。测定了粒径分布、zeta电位和表面含量等重要参数，证实了ALMWP与纳米颗粒表面的结合。负载紫杉醇（PTX）的ALMWP-NP表现出用于抗胶质母细胞瘤药物递送的期望的药代动力学和生物分布特征。细胞实验表明，ALMWP-NP通过脂筏介导的内吞和能量依赖的巨胞饮作用，显著增加C6细胞中MMP依赖的细胞蓄积，并改善PTX的细胞毒性。体外C6肿瘤球体摄取证实了ALMWP-NP的肿瘤穿透能力，体内成像和胶质瘤分布证明了其在胶质瘤中的特异性蓄积。改善的胶质瘤靶向和肿瘤渗透导致预期增强的体内抗胶质母细胞瘤作用：用ALMWP-NP-FTX处理的动物（携带颅内C6胶质瘤的裸鼠）比用盐水、Taxol（R）NP-FTX和LMWP-NP-PTX处理的动物存活显著更长。本研究为ALMWP-NP-PIX的胶质母细胞瘤靶向治疗提供了有力的证据，也为CPP在胶质瘤靶向治疗中的应用提供了重要的进展。(C)2012爱思唯尔有限公司版权所有。
By taking advantage of the dramatically upregulated expression of matrix metalloproteinases MMP-2 and MMP-9 in glioblastomas and the powerful transport ability of low molecular weight protamine (LMWP), we constructed an activatable low molecular weight protamine (ALMWP) and conjugated it to PEG-PCL nanoparticles (NP) to develop a 'smart' drug delivery system for enhanced targeted glioblastoma therapy. Important parameters such as particle size distribution, zeta potential and surface content were determined, which confirmed the conjugation of ALMWP to the surface of nanoparticle. ALMWP-NP loaded with paclitaxel (PTX) exhibited a desirable pharmacokinetic and biodistribution profiles for anti-glioblastoma drug delivery. Cellular experiments showed that ALMWP-NP exhibited significantly elevated MMP-dependent cellular accumulation in C6 cells via lipid raft-mediated endocytosis and energy-dependent macropinocytosis, and improved the cytotoxicity of PTX. In vitro C6 tumor spheroid uptake confirmed the tumor penetrating ability of ALMWP-NP, in vivo imaging and glioma distribution justified its specific accumulation in the glioma. The improved glioma-targeting and tumor penetration led to an anticipated enhanced in vivo anti-glioblastoma effect: animals (nude mice bearing intracranial C6 glioma) treated with ALMWP-NP-FTX survive significantly longer than those treated with saline, Taxol((R)) NP-FTX and LMWP-NP-PTX. The findings here offered strong evidence for the glioblastoma-targeting therapy of ALMWP-NP-PIX, and could also lead to a significant advancement in the application of CPPs for targeted therapy of glioma. (C) 2012 Elsevier Ltd. All rights reserved.