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    Expandible microparticle intracellular delivery system
    4.
    发明授权
    Expandible microparticle intracellular delivery system 失效
    可扩散的微粒细胞内递送系统

    公开(公告)号：US5952232A

    公开(公告)日：1999-09-14

    申请号：US156739

    申请日：1998-09-17

    申请人： James Edward Rothman

    发明人： James Edward Rothman

    IPC分类号： C12N15/09 ,  A61K9/14 ,  A61K31/7088 ,  A61K38/00 ,  A61K47/32 ,  A61K48/00 ,  A61P25/00 ,  A61P31/00 ,  A61P35/00 ,  A61P37/00 ,  C12N15/87 ,  C12N15/64

    CPC分类号： C12N15/87 ,  Y10S977/905 ,  Y10S977/906 ,  Y10S977/92

    摘要： The present invention relates to methods and compositions for delivery of a compound, most preferably a polynucleotide, into the cytoplasm of a cell by means of a microparticle, fabricated from a pH-sensitive hydrogel in collapsed phase, and having a size and physical characteristics compatible with uptake via a clathrin-coated pit on the cell surface. The trigger pH at which the hydrogel expands is lower than the physiological pH of the extracellular environment, allowing the microparticle, which comprises the compound to be delivered, to maintain its compact size prior to cellular uptake, thereby providing the additional benefit of protecting the comprised compound from degradation. This protective feature is particularly beneficial in embodiments in which a polynucleotide or a peptide is being delivered. Following uptake via a clathrin-coated pit, the microparticle then enters the intracellular endocytic pathway, where it is subjected to a progressive decrease in pH. Once the trigger pH for the hydrogel is reached, the microparticle increases its water content and expands, bursting its containing vesicle, and allowing its comprised compound to enter the cytoplasm. According to the invention, microparticle expansion and drug release may be achieved by natural mechanisms without requiring the addition of exogenous compounds, or the application of electric fields, etc. Moreover, with regard to embodiments involving polynucleotides, the present invention provides a means for traversing the plasma membrane and delivering the polynucleotide into the cytoplasm; in conventional transfection methods the plasma membrane, as well as intracellular membranes as occur in endosomes or lysosomes, constitute a formidable barrier to entry.

    摘要翻译： 本发明涉及通过在崩解阶段由pH敏感的水凝胶制成的具有大小和物理特性相容的微粒，将化合物，最优选多核苷酸递送至细胞的细胞质的方法和组合物 通过在细胞表面上通过网格蛋白涂覆的凹坑摄取。 水凝胶膨胀的触发pH低于细胞外环境的生理pH，允许包含化合物的微粒在细胞摄取之前保持其紧凑的尺寸，从而提供额外的益处，保护包含 化合物降解。 该保护特征在其中递送多核苷酸或肽的实施方案中是特别有益的。 在通过网格蛋白包被的凹坑摄取后，微粒然后进入细胞内内吞途径，在那里其进行pH逐渐降低。 一旦达到水凝胶的触发pH，微粒会增加其含水量并膨胀，使其含有囊泡爆裂，并使其包含的化合物进入细胞质。 根据本发明，可以通过天然机制实现微粒膨胀和药物释放，而不需要添加外源化合物，或施加电场等。此外，关于涉及多核苷酸的实施方案，本发明提供了一种用于穿过 质膜并将多核苷酸递送到细胞质中; 在常规转染方法中，质膜和内膜或溶酶体中发生的细胞膜构成进入的强大障碍。