Synthesis of TAT peptide-tagged PEGylated chitosan nanoparticles for siRNA delivery targeting neurodegenerative diseases
Synthesis of TAT peptide-tagged PEGylated chitosan nanoparticles for siRNA delivery targeting neurodegenerative diseases
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DOI：
10.1016/j.biomaterials.2012.10.013
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发表时间：
2013-01-01
期刊：
影响因子：
14
通讯作者：
Prakash, Satya
中科院分区：
文献类型：
--
作者：
Malhotra, Meenakshi;Tomaro-Duchesneau, Catherine;Prakash, Satya
将治疗性分子递送至脑以治疗神经退行性疾病（ND）是一项具有挑战性的任务。本文介绍了一种新的合成肽标记的聚乙二醇（PEG）酰化壳聚糖聚合物的方案，以开发用于ND的siRNA递送的纳米颗粒。具体而言，该手稿提出了一种简单的化学选择性共轭的单甲氧基PEG，在C2羟基的壳聚糖聚合物，与共轭的PEG的细胞穿透肽，转录的反式激活剂。合成的壳聚糖-达特聚合物用于形成约5 nm的纳米颗粒，复合待递送到神经元细胞（Neuro 2a）中的siRNA，无毒性/毒性最小。合成过程中形成的各种中间体和最终产物用H-1核磁共振和傅立叶变换红外光谱进行表征。使用透射电子显微镜的纳米粒子的形态细节进行了研究。在体外建立的过度表达共济失调蛋白的ND脊髓小脑共济失调（SCA 1）模型中，测试纳米颗粒递送针对共济失调蛋白-1基因的功能性siRNA。结果表明转染48小时后成功抑制了SCA 1蛋白。这项研究的结果有可能在ND像SCA，帕金森氏症，阿尔茨海默氏症和其他。皇冠版权所有（C）2012由爱思唯尔有限公司出版。保留所有权利。
Delivery of therapeutic molecules to the brain for the treatment of Neurodegenerative diseases (ND) is a challenging task. This manuscript introduces a novel scheme of synthesizing peptide-tagged polyethylene glycol (PEG)ylated chitosan polymer to develop nanoparticles for siRNA delivery for use in ND. Specifically, this manuscript proposes a facile chemoselective conjugation of monomethoxy PEG, at the C2 hydroxyl group of chitosan polymer, with conjugation of PEG to a cell-penetrating peptide, Trans-Activator of Transcription. The synthesized Chitosan-PEG-TAT polymer was used to form the nanoparticles of approximately 5 nm, complexing siRNA to be delivered in neuronal cells (Neuro 2a), with no/minimal toxicity. The various intermediates and the final product formed during the synthesis were characterized using H-1 Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy spectra. The morphological details of the nanoparticles were studied using Transmission Electron Microscopy. The nanoparticles were tested to deliver a functional siRNA against the Ataxin-1 gene in an in-vitro established model of a ND Spinocerebellar ataxia (SCA1) over-expressing ataxin protein. The results indicate successful suppression of the SCA1 protein following 48 h of transfection. Result of this study has potential in ND like SCA, Parkinson's, Alzheimer's and others. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.