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Development of the targetable and fusogenic polyethyleneglycol liposomes for gene delivery

用于基因递送的可靶向融合聚乙二醇脂质体的开发

基本信息

批准号：
08672568
负责人：
MARUYAMA Kazuo
金额：
$ 1.41万
依托单位：
TEIKYO UNlVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672568/
关键词：
DDS liposome gene therapy polyethyleneglycol membrane fusion transferrin ターゲティング

项目摘要

For the purpose of intracellular targeting carrier by systemic administration, PEG-liposomes conjugating transferrin (TF) at the distal ends of PEG chain were newly prepared. Biodistribution of TF-PEG liposome was examined in the colon 26 bearing mice. TF-PEG liposome were prolonged in the circulation and highly accumulated into the tumor tissue. After extravasation, TF-PEG liposome retains the specific binding ability to tumor cell surface. Uptake of TF-PEG liposome was examined by electron microscopy. TF-PEG liposome was localized at the cell surface, coated pits and endosome. These results show TF-PEG liposome was bound and internalized by endocytosis. Such liposomes should be useful for intracellular targeting carrier at the way of systemic administration.We prepared a new fusogenic liposomes modified with succinylated poly(glycidol)(sucPG), which is a polyethyleneglycol derivatives with carboxyl groups and alkyl groups. Furthermore, we prepared sucPG immunoliposomes, which were conjugated with TF, to gain the binding and endocytotic internalization to the tumor cells. SucPG liposomes (eggPC : sucPG=4 : 1 w/w) showed fusion ability under acidic condition such as pH4.O.From the fluorescent microscopic observation, it was shown that TF-sucPG irnmunoliposomes bound to colon26 tumor cells and induced endocytosis. These results suggested the occurrence of fusion between sucPG immunoliposomes and endosome membrane. TF-sucPG immunoliposomes have targeting and fusion ability to the Colon26 tumor cells. Thus we have succeeded to develop the targetable and fusogenic liposomes. TF-sucPG immunoliposome could be useful for as a vector in gene therapy.

为了通过全身给药实现细胞内靶向载体的作用，新制备了聚乙二醇链末端结合转铁蛋白的聚乙二醇脂质体。考察了转移因子-聚乙二醇脂质体在结肠26荷瘤小鼠体内的分布。转移因子-聚乙二醇脂质体在循环中的时间延长，并在肿瘤组织中高度蓄积。经外渗后，TF-PEG脂质体保留了与肿瘤细胞表面的特异性结合能力。用电子显微镜观察TF-PEG脂质体的摄取。转移因子-聚乙二醇脂质体定位于细胞表面、包被的凹坑和内吞体内。这些结果表明，TF-PEG脂质体是通过内吞作用结合和内化的。这种脂质体有望成为全身给药的细胞内靶向载体。我们制备了一种新型的丁二酸化聚缩水甘油修饰的融合脂质体，它是一种带有羧基和烷基的聚乙二醇衍生物。此外，我们还制备了SucPG免疫脂质体，并将其与Tf偶联，以获得与肿瘤细胞的结合和内吞作用。SucPG脂质体(eggPC：suPG=4：1w/w)在pH4.0等酸性条件下表现出融合能力。荧光显微镜观察表明，Tf-suPG免疫脂质体与肿瘤细胞结合并诱导内吞。这些结果表明，SucPG免疫脂质体与内吞体膜发生了融合。Tf-suPG免疫脂质体具有靶向和融合肿瘤细胞的能力。因此，我们成功地研制出了靶向性和融合性脂质体。Tf-SucPG免疫脂质体可作为基因治疗的载体。