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Enhancing intracranial delivery of clinically relevant non-viral gene vectors

机译：增强临床相关非病毒基因载体的颅内递送

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摘要

Gene therapy is a promising strategy for the management of various neurological disorders that do not respond adequately to conventional therapeutics. The development of gene vectors with favorable safety profiles that can achieve uniform distribution and high-level transgene expression in the brain remains challenging. The rod-shaped, non-viral gene delivery platform based on poly-L-lysine (PLL) conjugated to a single segment of polyethylene glycol (PEG) has shown safe transfection in human nares and mouse brains in vivo. However, we have previously demonstrated that a denser PEG coating is required for rapid diffusion of nanoparticles in the brain extracellular space. Here, we engineered a densely PEGylated version of this platform based on PLL polymers conjugated to branched PEG via alkyne-azide cycloaddition. We found that the newly developed gene vectors rapidly diffused in the brain parenchyma, providing significantly improved vector distribution and overall transgene expression in vivo compared to the previously developed platform. These brain-penetrating DNA nanoparticles exhibited enhanced cellular uptake presumably due to their ellipsoidal morphology. By simultaneously improving delivery to target cells and subsequent transfection, our densely PEGylated PLL DNA nanoparticles can provide widespread, high levels of transgene expression, essential for effective targeting of highly disseminated brain diseases.
机译：基因疗法是管理各种神经系统疾病的有希望的策略，这些疾病不会充分对常规治疗剂进行充分响应。具有良好安全谱的基因载体的发展，可以实现大脑中均匀分布和高水平转基因表达的含量仍然具有挑战性。基于聚乙二醇（PEG）缀合的聚-L-赖氨酸（PLL）的棒状非病毒基因递送平台已在体内的人鼻腔和小鼠大脑中显示出安全转染。然而，我们之前证明了更密集的PEG涂层需要在脑细胞外空间中快速扩散纳米颗粒。在这里，我们基于通过炔氧化物环形编辑将PLL聚合物缀合的PLL聚合物来设计该平台的密度PEG化版本。我们发现，与先前开发的平台相比，新开发的基因载体在脑实质中迅速扩散，在体内提供显着改善的载体分布和整体转基因表达。由于其椭圆形态，这些脑穿透的DNA纳米颗粒具有增强的细胞摄取。通过同时改善靶细胞和随后的转染，我们密集的PEG化的PLL DNA纳米颗粒可以提供广泛的高水平的转基因表达，对于有效靶向高度易溶性脑疾病是必不可少的。

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  • 来源
    《RSC Advances》 |2016年第48期|共10页
  • 作者

    Berry Sneha; Mastorakos Panagiotis; Zhang Clark; Song Eric; Patel Himat; Suk Jung Soo; Hanes Justin;

  • 作者单位

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

    Johns Hopkins Univ Sch Med Wilmer Eye Inst Ctr Nanomed Baltimore MD 21205 USA;

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  • 正文语种 eng
  • 中图分类 化学;
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