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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted gene transfer into hepatoma cells with lipopolyamine-condensed DNA particles presenting galactose ligands: a stage toward artificial viruses.
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Targeted gene transfer into hepatoma cells with lipopolyamine-condensed DNA particles presenting galactose ligands: a stage toward artificial viruses.

机译：具有半乳糖配体的脂多胺浓缩的DNA颗粒将靶向基因转移到肝癌细胞中：迈向人造病毒的阶段。

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Optimal in vitro gene delivery with cationic lipids requires an excess of cationic charges with respect to DNA phosphates. In these conditions, in vivo delivery will be hampered by interference from cationic lipid-binding macromolecules either circulating or in the extracellular matrix. To overcome this problem, we are developing a modular transfection system based on lipid-coated DNA particles reminiscent of enveloped viruses. The particle core consists of the lipopolyamine-condensed nucleic acid in an electrically neutral ratio to which other synthetic lipids with key viral properties are hydrophobically adsorbed. As a first result, we have found that a good transfection level can be achieved simply with the neutral core particle, provided a zwitterionic lipid (dioleoyl phosphatidylethanolamine) is added to completely coat the DNA. Addition of lipids bearing a fusogenic or a nuclear localization peptide head group to the particles does not significantly improve an already efficient system, in contrast to polylysine-based gene transfer methods that rely on lysosomotropic or fusogenic agents to be effective. This emphasizes the distinctive properties of the lipopolyamines, including cell membrane destabilization, endosome buffering capacity, and possibly nuclear tropism. Most importantly, addition of lipids with a triantennary galactosyl residue drives the neutral nucleolipidic particles to the asialoglycoprotein receptor of human hepatoma HepG2 cells: Transfection increases approximately 1000-fold with 25% galactolipid. This receptor-mediated process is saturable and slightly less efficient than receptor-independent transfection obtained in vitro with a large excess of cationic lipid alone. Yet, electrically silent particles may provide an attractive solution for gene transfer in vivo where their external saccharide coat should allow them to diffuse within the organism and reach their target cells.
机译：与DNA磷酸酯相比，阳离子脂质的最佳体外基因递送需要过量的阳离子电荷。在这些条件下，体内传递将受到循环中或细胞外基质中阳离子脂质结合大分子干扰的阻碍。为了克服这个问题，我们正在开发一种基于脂质包裹的DNA颗粒的模块化转染系统，该颗粒使人联想到包膜病毒。颗粒核由电中性比的脂多胺缩合核酸组成，具有关键病毒特性的其他合成脂质被疏水性吸附到该核酸上。作为第一个结果，我们发现只要添加两性离子脂质（二油酰基磷脂酰乙醇胺）以完全覆盖DNA，中性核心颗粒就可以轻松实现良好的转染水平。与依赖溶溶同性或融合剂的基于聚赖氨酸的基因转移方法有效相比，将带有融合或核定位肽头部基团的脂质添加到颗粒中并不能显着改善已经有效的系统。这强调了脂多胺的独特特性，包括细胞膜失稳，内体缓冲能力以及可能的核趋向性。最重要的是，添加具有三触角半乳糖残基的脂质会将中性核糖核酸颗粒驱动至人肝癌HepG2细胞的去唾液酸糖蛋白受体：25％的半乳糖脂使转染增加约1000倍。该受体介导的过程是饱和的，并且其效率比体外用单独大量过量的阳离子脂质获得的非受体依赖的转染略低。然而，电沉默颗粒可以为体内基因转移提供有吸引力的解决方案，其中其外部糖衣可以使它们在生物体内扩散并到达其靶细胞。

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