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首页> 外文期刊>Acta biomaterialia >Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo
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Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo

机译：通过两亲富勒烯衍生物通过两亲富勒烯衍生物可见光切换的细胞溶质释放，以增强体外和体内RNAi疗效

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摘要

Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C-60-Dex-NH2) for efficient and controllable siRNA delivery. To synthesize C-60-Dex-NH2, terminally aminated dextran was conjugated to C-60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C-60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (C-13, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C-60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C-60-Dex-NH2 in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C-60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C-60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice.
机译：由于它们在非免疫反应中的性能，合成期间的定制和低成本与病毒载体相比，阳离子大分子具有吸引力，并且由于它们在非免疫反应中的性能而具有小的干扰RNA（siRNA）载体。然而，它们的低转染效率大大阻碍了它们在临床实践和学术研究中的应用，这主要是归因于siRNA /阳离子大分子复合物的低容量来逃避溶酶体。为了解决这一挑战，我们设计了一种用于高效可控的siRNA递送的两亲富勒烯衍生物（C-60-DEX-NH2）。为了合成C-60-DEX-NH2，将终止胺胺化的葡聚糖缀合至C-60。通过将乙二胺与葡聚糖共价将乙二胺进一步巩固缀合物。用元素分析，凝胶渗透色谱法，固态核磁共振（C-13，HPDEC），琼脂糖凝胶电泳和动态光散射检查C-60-DEX-NH2的物理化学特性。在人乳腺癌细胞系MDA-MB-231中评价siRNA / C-60-DEX-NH2复合物的细胞毒性，细胞吸收，细胞内分布和体外RNA干扰（RNAi）。在皮下肿瘤携带的小鼠中评估由C-60-DEX-NH2介导的RNAi效率。结果表明，C-60-DEX-NH2具有特异性两亲性骨架，可以在水中形成胶束状骨料结构，这可以防止siRNA通过反应性氧（ROS）破坏。当暴露于可见光时，C-60-DEX-NH2可以引发可控制的ROS生成，这可能破坏溶酶体膜，促进溶酶体逸出，并在体外和体内增强siRNA的基因沉默效率。在MDA-MB-231-EGFP细胞中，基因沉默效率最高可达到53％，并且在4T1-GFP-LUC2肿瘤瘤小鼠中达到69％。

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  • 来源
    《Acta biomaterialia》 |2017年第2017期|共12页
  • 作者

    Wang Jing; Xie Lifei; Wang Tao; Wu Fengxin; Meng Jie; Liu Jian; Xu Haiyan;

  • 作者单位

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

    Chinese Acad Med Sci Peking Union Med Coll Sch Basic Med Inst Basic Med Sci Beijing Peoples R;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 普通生物学;
  • 关键词

    Small interfering RNA; Lysosome escape; Fullerene; Cationized dextran; Light sensitive;

    机译：小干扰RNA;溶酶体逃生;富勒烯;阳离子化的葡聚糖;光敏感;

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