A hybrid siRNA delivery complex for enhanced brain penetration and precise amyloid plaque targeting in Alzheimer’s disease mice

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• 作者：Xiaoyao Zheng ; Xiaoying Pang ; Peng Yang ; Xu Wan ; Yue Wei ; Qian Guo ; Qizhi Zhang ; ^{qzzhang@fudan.edu.cn} ; Xinguo Jiang
• 关键词：Cationic hybrid complex ; siRNA delivery ; Blood-brain barrier (BBB) ; Amyloid plaque ; Alzheimer&rsquo ; s disease
• 刊名：Acta Biomaterialia
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：49
• 期：Complete
• 页码：388-401
• 全文大小：4736 K
• 卷排序：49

文摘

To realize the therapeutic potential of gene drugs for Alzheimer’s disease (AD), non-invasive, tissue-specific and efficient delivery technologies must be developed. Here, a hybrid system for amyloid plaques targeted siRNA delivery was formed by PEGylated Poly(2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) conjugated with two d-peptides, a CGN for brain penetration and a QSH for β-amyloid binding. The hybrid complex CQ/siRNA, composed of 25% MPEG-PDMAEMA, 50% CGN-PEG-PDMAEMA and 25% QSH-PEG-PDMAEMA, showed negligible cytotoxicity and could protect siRNA from enzyme degradation. Being taken up by neuron cells, the complexes could escape from lysosomes, release siRNA in the cytoplasm and thus producing effective gene silence (down-regulated protein level to 18.5%). After intravenous injection, CQ/siRNA penetrated into the brain in an intact form and located around the plaques in transgenic AD mice. The precisely amyloid plaques delivery resulted in increased therapeutic activities, which was demonstrated by the strong mRNA (36.4%) knockdown of BACE1 (a therapeutic target of AD), the less yield of enzyme-digested products sAPPβ (−42.6%), as well as the better neurons protection than the single component complexes. In conclusion, the hybrid complex could efficiently and precisely deliver an siRNA to the AD lesion and might be a potential candidate for gene therapy for AD.Statement of SignificanceThe gene delivery system achieving high brain penetration and lesion region accumulation was first applied to treat AD, and the preparation exhibited a significantly better neuroprotective effect than that modified with a single ligand. The intracellular process of which the complexes escape from lysosomes and release the siRNA in cytoplasm was revealed. The brain targeting and amyloid plaque binding ability of the complex were systemic evaluated, and the in vivo co-location experiments provided a direct evidence of the precise delivery of the siRNA to the amyloid plaques. One of the targeting ligands, CGN, which was a retro–inverso modified peptide to achieve better affinity to the BBB, was first applied to the brain targeting system.