A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment
A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment
复制标题
一种穿越血脑屏障的非病毒自杀基因传递系统，用于非侵入性胶质瘤靶向治疗
DOI：
10.1016/j.jconrel.2016.10.027
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发表时间：
2016-12-10
影响因子：
10.8
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
--
作者：
Gao, Shiqian;Tian, Huayu;Chen, Xuesi
单纯疱疹病毒I型胸苷激酶基因（HSV-TK）是治疗多形性胶质母细胞瘤（GBM）的有效策略。然而，其生物安全性风险限制了其在临床上的应用。在这项工作中，聚（L-赖氨酸）接枝聚乙烯亚胺（PEI-PLL），它结合了高转染效率的聚乙烯亚胺和良好的生物降解性的聚（L-赖氨酸），作为非病毒载体骨架。血管肽素-2（Angiopep-2）是一种跨血脑屏障（BBB）和胶质瘤靶向的双功能肽，通过聚乙二醇（PEG）与PEI-PLL偶联，命名为PPA。首次确定了PPA/DNA复合物纳米粒（PPA NPs）的最佳转染比例。接下来，通过细胞摄取和转染分析证实PPA NP的胶质瘤靶向。体内成像研究表明，PPA NPs不仅可以穿透血脑屏障，而且可以通过全身给药在纹状体和皮质中蓄积。此外，PPA/HSV-TK NPs通过抑制增殖和诱导凋亡在侵袭性原位人GBM小鼠模型中显示出显著的抗胶质瘤作用和存活益处（p < 0.05 vs对照）。本研究首次证明阳离子聚合物PPA可以作为一种有效的基因载体穿越血脑屏障，并创新性地为神经胶质瘤的无创自杀基因治疗提供了一种潜在的非病毒纳米药物。(C)© 2016 Elsevier B. V.版权所有。
Herpes simplex virus type I thymidine kinase gene (HSV-TK) in viral vector is a promising strategy against glioblastoma multiforme (GBM). However, the biosafety risk restricts its application in clinic. In this work, poly (L-lysine)-grafted polyethylenimine (PEI-PLL), which combines the high transfection efficiency of polyethylenimine and the good biodegradability of poly (L-lysine), was adopted as the non-viral vector backbone. Angiopep-2, a blood brain barrier (BBB) crossing and glioma targeting bifunctional peptide was conjugated on PEI-PLL via polyethyleneglycol (PEG) and designated as PPA. The optimal transfection ratio of PPA/DNA complexes nanoparticles (PPA NPs) was firstly characterized. Next, the glioma targeting of the PPA NPs was confirmed through cellular uptake and transfection analysis. The in vivo imaging studies demonstrated that the PPA NPs could not only penetrate BBB but also accumulate in striatum and cortex via systemic administration. Moreover, the PPA/HSV-TK NPs showed remarkably anti-glioma effect and survival benefit in an invasive orthotopic human GBM mouse model through inhibiting proliferation and inducing apoptosis (p < 0.05 vs control). This study firstly illustrated that the cationic polymer PPA could be exploited as an efficient gene vector to cross the BBB, and innovatively provided a potential non-viral nanomedicine for noninvasive suicide gene therapy in the glioma treatment. (C) 2016 Elsevier B.V. All rights reserved.