Polyplex nanomicelle promotes hydrodynamic gene introduction to skeletal muscle
Polyplex nanomicelle promotes hydrodynamic gene introduction to skeletal muscle
复制标题
DOI：
10.1016/j.jconrel.2009.12.014
复制
发表时间：
2010-04-02
影响因子：
10.8
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Itaka, Keiji;Osada, Kensuke;Kataoka, Kazunori
骨骼肌是基因治疗的一个有趣的靶点。为了在骨骼肌中实现有效的基因导入，一种通过静脉注射质粒DNA(PDNA)并瞬时分离肢体的流体动力学方法引起了人们的关注。在本研究中，我们证明了由聚乙二醇单嵌段多聚阳离子和PDNA组成的复合纳米胶束具有良好的骨骼肌基因导入能力。对肌肉中荧光素酶表达的评估表明，与裸露的pDNA相比，纳米胶束提供了更高和持续的转基因表达谱。使用视频率共聚焦成像系统的实时体内成像表明，纳米胶束在细胞内环境中表现出耐受性，导致了缓慢但持续的转基因表达。与裸露的pDNA相比，纳米胶束在肌肉中诱导的肿瘤坏死因子α诱导更少，这表明基于纳米胶束的基因输送到骨骼肌是安全的。此外，通过将表达可溶性形式的血管内皮生长因子受体-1(sFlt-1)的pDNA引入骨骼肌，该纳米胶束显示了近一个月的显著抑制肿瘤生长的作用，以获得抑制肿瘤生长的血管生成作用。这一持续效应的特点为基因治疗提供了重要的优势，特别是在成本效益和高依从性方面。这些结果表明，利用复合纳米胶束系统将流体动力学基因导入骨骼肌具有有效的基因治疗的潜力。(C)2009爱思唯尔B.V.保留所有权利。
Skeletal muscle is an interesting target for gene therapy. To achieve effective gene introduction in skeletal muscle, a hydrodynamic approach by intravenous injection of plasmid DNA (pDNA) with transient isolation of the limb has attracted attention. In this study, we demonstrated that polyplex nanomicelle, composed of poly(ethyleneglycol) (PEG)-block-polycation and pDNA, showed excellent capacity of gene introduction to skeletal muscle. The evaluation of luciferase expression in the muscle revealed that the nanomicelle provided higher and sustained profiles of transgene expression compared with naked pDNA. Real-time in vivo imaging using a video-rate confocal imaging system suggested that the nanomicelle showed tolerability in the intracellular environment, resulting in the slow but sustained transgene expression. The nanomicelle induced less TNF alpha induction in the muscle than naked pDNA, indicating the safety of nanomicelle-based gene delivery into the skeletal muscle. Moreover, the nanomicelle showed significant tumor growth suppression for almost a month by introducing a pDNA expressing a soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1) to skeletal muscle to obtain anti-angiogenic effect on tumor growth. This feature of sustained effect gives an important advantage of gene therapy, especially on the points of cost effectiveness and high compliance. These results suggest that the hydrodynamic gene introduction to skeletal muscle using polyplex nanomicelle system possesses the potential for effective gene therapy. (C) 2009 Elsevier B.V. All rights reserved.