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1. 发明申请

WO0180900A3 ENHANCED STABILISED PLASMID-LIPID PARTICLE-MEDIATED TRANSFECTION USING ENDOSOMAL MEMBRANE 审中-公开
标题翻译：使用内皮膜增强稳定的PLASMID-脂质粒细胞介导的转染
公开(公告)号：WO0180900A3
公开(公告)日：2003-04-24
申请号：PCT/CA0100555
申请日：2001-04-20
申请人： UNIV BRITISH COLUMBIA , LAM ANGELA M I , PALMER LORNE R , CULLIS PIETER R
发明人： LAM ANGELA M I , PALMER LORNE R , CULLIS PIETER R
IPC分类号： C12N15/09 , A61K9/127 , A61K47/04 , A61K47/18 , A61K47/44 , A61K47/48 , A61K48/00 , A61P43/00 , C12N15/88
CPC分类号： C12N15/88 , A61K9/1272
摘要： The present invention provides effective compositions, methods and uses for delivering nucleic acids to cells. The inventive compositions and methods are based upon the surprising discovery that the presence of an endosomal membrane destabiliser in a lipid formulation leads to a dramatic increase in transfection efficiency. The present compositions and methods can be used in vitro or in vivo, and can be used to increase the transfection efficiency of any cell type, including mammalian cells (e.g., humans). In certain embodiments, the conjugated lipid that inhibits aggregation is a "cationic polymer lipid" (CPL). In preferred aspects, the CPL has the formula (I). In formula (I), A is a lipid moiety, W is a hydrophilic polymer, and Y is a polycationic moiety. In certain preferred embodiments, Y is selected from lysine, arginine, asparagine, glutamine, and combinations thereof. In another embodiment, the present invention provides a method for introducing a nucleic acid into a cell, comprising contacting the cell with a nucleic acid-lipid particle composition, wherein the particle comprises a cationic lipid, a conjugated lipid that inhibits aggregation of particles, a nucleic acid; and an endosomal membrane destabilizer. The endosomal membrane destabilizer can be inside the particle, outside the particle, or both inside and outside the particle. In certain embodiments, the endosomal membrane destabilizer contacts the cell before the particle, after the particle, simultaneously or combinations thereof. In still another embodiment, the present invention provides a method for inducing HII phase structure in a lipid bilayer, comprising contacting the lipid bilayer with an endosomal membrane destabilizer, thereby inducing HII phase structure in the lipid bilayer. In certain aspects, the endosomal membrane destabilizer (e.g., Ca ion) acts synergistically or additively with low levels of the cationic lipid to trigger HII phase formation.
摘要翻译：本发明提供了将核酸递送至细胞的有效组合物，方法和用途。本发明的组合物和方法基于惊人的发现，即在脂质制剂中存在内体膜去稳定剂导致转染效率的显着增加。本发明的组合物和方法可以在体外或体内使用，并且可以用于增加任何细胞类型（包括哺乳动物细胞（例如人））的转染效率。在某些实施方案中，抑制聚集的共轭脂质是“阳离子聚合物脂质”（CPL）。在优选的方面，CPL具有式（I）。在式（I）中，A是脂质部分，W是亲水性聚合物，Y是聚阳离子部分。在某些优选实施方案中，Y选自赖氨酸，精氨酸，天冬酰胺，谷氨酰胺及其组合。在另一个实施方案中，本发明提供了将核酸引入细胞的方法，包括使细胞与核酸 - 脂质颗粒组合物接触，其中所述颗粒包含阳离子脂质，抑制颗粒聚集的共轭脂质，核酸; 和内体膜去稳定剂。内体膜去稳定剂可以在颗粒内部，颗粒外部，或颗粒内部和外部。在某些实施方案中，内体膜去稳定剂在颗粒之前，颗粒之后，同时或其组合接触细胞。在另一个实施方案中，本发明提供了用于在脂质双层中诱导HII相结构的方法，包括使脂质双层与内体膜去稳定剂接触，从而在脂质双层中诱导HII相结构。在某些方面，内体膜去稳定剂（例如Ca ++）与低水平的阳离子脂质协同或附加地起作用以触发HII相形成。

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