CN104109241A - 共价疏水修饰的聚乙烯亚胺及其制备方法和应用 - Google Patents
共价疏水修饰的聚乙烯亚胺及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,涉及共价疏水修饰的聚乙烯亚胺及其制备方法和应用。本发明对转染试剂聚乙烯亚胺进行疏水性共价修饰,改变该阳离子聚合物的部分理化性质,制得共价疏水修饰的聚乙烯亚胺;该共价疏水修饰的聚乙烯亚胺具有式(Ⅰ)的结构。经测试结果表明,所述共价疏水修饰的聚乙烯亚胺对核酸的转染效率较未修饰的聚乙烯亚胺明显提高;其可制备转染试剂,用于动物或者人体水平的转基因动物或者基因治疗,或用于细胞水平的核酸转染。
Description
技术领域
本发明属于生物医药技术领域,涉及共价疏水修饰的聚乙烯亚胺及其制备方法和应用;尤其涉及共价疏水修饰的聚乙烯亚胺在核酸转染中的应用。
背景技术
目前,基因治疗、转基因动物操作中,重要的环节是将基因转入真核细胞,而将基因转入真核细胞的技术可归纳为三种:(1)生化方法转染;(2)物理方法转染;(3)病毒介导的转化。所述的生化方法转染中常用的生化试剂有:磷酸钙,二乙氨乙基-葡聚糖,阳离子脂质体和阳离子聚合物。已知聚乙烯亚胺(polylethyleneimine, PEI)是最常用的阳离子聚合物转染试剂(美国专利6013240);其作用机理推测为带负电荷的核酸和PEI静电吸附形成PEI-DNA (PEI-RNA) 复合物,然后该复合物和带负电荷的细胞膜静电吸附,再后通过胞吞作用转入真核细胞内。美国专利6013240公开了阳离子聚合物PEI和阳离子脂质体DOGS或DOPE能够协同作用提高转染效率;但实际使用中,仍发现其存在转染效率不高的缺陷,尚需对其进行改进。
因此,本发明的申请人拟提供一种共价疏水修饰的聚乙烯亚胺;其与细胞膜不仅有静电吸附作用,还有疏水相互作用,使转染复合物更容易进入真核细胞内。迄今为止,尚未见有关共价疏水修饰的聚乙烯亚胺及其制备方法的报道。
发明内容
本发明的目的是提供一种共价疏水修饰的聚乙烯亚胺及其制备方法和应用;尤其涉及该共价疏水修饰的聚乙烯亚胺在核酸转染中的应用;所述共价修饰的聚乙烯亚胺能提高转染效率,可用于细胞核酸转染、转基因动物、基因治疗等。
本发明中,利用有机化学手段对聚乙烯亚胺进行修饰,使其带有一定的疏水性,同时在水溶液(或者PBS,DMEM培养基)中可溶或者部分可溶;经测试结果显示,修饰后的聚乙烯亚胺较未修饰的聚乙烯亚胺对真核细胞的转染效率有显著提高,所述疏水修饰后的聚乙烯亚胺与细胞膜不仅有静电吸附作用,还有疏水相互作用,使转染复合物更容易进入真核细胞内。
具体而言,本发明的共价疏水修饰的聚乙烯亚胺,对转染试剂聚乙烯亚胺(美国专利6013240)进行疏水性共价修饰,改变其中的阳离子聚合物的部分理化性质;该共价疏水修饰的聚乙烯亚胺的结构式如式(Ⅰ)所示,
(Ⅰ)
其中,
修饰基团为长度在1-20之间的直链或者支链烃基,可为饱和烃基也可为不饱和烃基,或为其他形式的疏水性的集团,如胆固醇等;
修饰方式可为氨基和羧基之间的缩合反应,也可为其他方式的共价修饰;
修饰位点主要为聚乙烯亚胺上的氨基,也可在碳原子上;
共价修饰的烃基和聚乙烯亚胺单体的摩尔比为1:200~1:1;本发明的实施例中优选摩尔比为1:20~1:5,效果最为明显。
本发明中,所述共价疏水修饰的聚乙烯亚胺包括任意聚合度的形式,尤其是分子量在15-180kD的聚乙烯亚胺;
本发明中,所述聚乙烯亚胺可为支链聚乙烯亚胺,也可为支链聚乙烯亚胺。
本发明的另一目的是提供所述共价疏水修饰的聚乙烯亚胺的制备方法,其特征在于,其包括步骤:
(1)共价修饰聚乙烯亚胺
聚乙烯亚胺溶于乙醇,油酸或者其他形式的脂肪所或者胆酸溶于乙醇,在添加羰基二咪唑(CDI)条件下,室温反应两个小时;
(2)纯化修饰后的聚乙烯亚胺
将上述反应产物用十倍体积甲苯稀释,冰上放置2h,抽滤,用冰冷甲苯洗两遍,收集洗涤后的固体,冷冻干燥;
(3)配置修饰后聚乙烯亚胺溶液
用双蒸水或者PBS溶液或者TBS溶液溶解修饰后的聚乙烯亚胺,配成浓度为1mg/ml的储液,若溶解性不佳时,还可用稀盐酸慢慢降低溶液的pH值;
(4)用修饰的聚乙烯亚胺转染质粒到真核细胞
500ul opti-MEM中加10ug 质粒,室温孵育5min;500ul opti-MEM中加20ul 配置的修饰聚乙烯亚胺溶液,室温孵育5min;上述溶液混合室温孵育20min,然后混合液慢慢滴加到细胞培养基,轻轻混匀,于37 ℃, 5% CO2细胞培养箱中培养。
本发明的所述共价疏水修饰的聚乙烯亚胺与现有技术中未修饰的聚乙烯亚胺相比较,具有以下优点:
(1) 性状稳定,保存周期长;
(2)在测试细胞中,其转染效率较未修饰聚乙烯亚胺有明显提高;
(3) 成本低廉。
本发明对转染试剂聚乙烯亚胺(美国专利6013240)进行疏水性共价修饰,改变该阳离子聚合物的部分理化性质,制得共价疏水修饰的聚乙烯亚胺;经测试结果显示,其核酸的转染效率明显提高;所述共价疏水修饰的聚乙烯亚胺可制备转染试剂,用于动物或者人体水平的转基因动物或者基因治疗,或可用于细胞水平的核酸转染,所述核酸包括DNA和RNA,具体形式包括环行、线性、发卡结构等。
附图说明
图1为在荧光显微镜下观察,用未修饰的聚乙烯亚胺和修饰的聚乙烯亚胺分别转染293T细胞、MCF-7细胞、Hela细胞、HepG2细胞的图片。
图2显示了用未修饰的聚乙烯亚胺和修饰的聚乙烯亚胺分别转染293T细胞、MCF-7细胞、Hela细胞、HepG2细胞的细胞裂解液荧光强度。
具体实施方式
实施例1:聚乙烯亚胺和油酸的缩合反应制备油酸修饰的聚乙烯亚胺
配置油酸的乙醇溶液2mg/ml, 聚乙烯亚胺的乙醇溶液2mg/ml,油酸溶液和聚乙烯亚胺溶液各取5ml混合,在烧杯中室温电磁搅拌;羰基二咪唑溶于乙醇配置5mg/ml溶液,取1ml慢慢滴加到搅拌的溶液中,室温反应2h;
反应产物用甲苯稀释到100ml,置于冰水混合物中2h,抽滤过滤,用冰冷甲苯洗涤2次,收集固体冷冻干燥;
称取干燥的修饰后的聚乙烯亚胺,溶于双蒸水中,配置成1mg/ml的溶液,用稀盐酸调节pH值至6.0,继续搅拌是固体完全溶解,无菌滤器过滤除菌分装备用。
实施例2:修饰聚乙烯亚胺转染带EGFP标记的质粒到真核细胞
用未修饰的聚乙烯亚胺和修饰的聚乙烯亚胺分别转染293T细胞,MCF-7细胞,Hela细胞,HepG2细胞;质粒带绿色荧光标记,48h后,在荧光显微镜下观察细胞图片,结果如图1所示,修饰后的聚乙烯亚胺较未修饰的聚乙烯亚胺的转染效率明显提高。
实施例3:修饰聚乙烯亚胺转染荧光素酶质粒到真核细胞
用未修饰的聚乙烯亚胺和修饰的聚乙烯亚胺分别转染293T细胞,MCF-7细胞,Hela细胞,HepG2细胞;质粒带荧光素酶,48h后,检测细胞裂解液荧光强度,结果如图2所示,修饰后的聚乙烯亚胺显著提高了质粒转染真核细胞的水平。
Claims (10)
1.一种共价疏水修饰的聚乙烯亚胺,其结构式如式(Ⅰ)所示,
(Ⅰ)
其中,
修饰基团为长度在1-20之间的直链或者支链烃基,选自饱和烃基、不饱和烃基、或其他形式的疏水性的集团;
修饰方式选自氨基和羧基之间的缩合反应、或其他方式的共价修饰;
修饰位点为聚乙烯亚胺上的氨基、或碳原子;
共价修饰的烃基和聚乙烯亚胺单体的摩尔比为1:200~1:1。
2.按权利要求1所述的共价疏水修饰的聚乙烯亚胺,其特征在于,所述共价修饰的烃基和聚乙烯亚胺单体的摩尔比为1:20~1:5。
3.按权利要求1所述的共价疏水修饰的聚乙烯亚胺,其特征在于,所述共价疏水修饰的聚乙烯亚胺其分子量为15-180kD。
4.按权利要求1所述的共价疏水修饰的聚乙烯亚胺,其特征在于,所述聚乙烯亚胺选自支链聚乙烯亚胺,或支链聚乙烯亚胺。
5.按权利要求1所述的共价疏水修饰的聚乙烯亚胺,其特征在于,所述其他形式的疏水性的集团是胆固醇。
6.制备权利要求1的共价疏水修饰的聚乙烯亚胺的方法,其特征在于,其包括步骤:
(1)共价修饰聚乙烯亚胺
聚乙烯亚胺溶于乙醇,油酸或者其他形式的脂肪酸或者胆酸溶于乙醇,添加羰基二咪唑(CDI),室温反应两个小时,制得共价疏水修饰的聚乙烯亚胺;
(2)纯化修饰后的聚乙烯亚胺
将上述反应产物用10倍体积甲苯稀释,冰上放置2h,抽滤,用冰冷甲苯洗两遍,收集洗涤后的固体,冷冻干燥;
(3)配置修饰后聚乙烯亚胺溶液
用双蒸水或者PBS溶液或者TBS溶液溶解修饰后的聚乙烯亚胺,配成浓度为1mg/ml的储液,制得共价疏水修饰的聚乙烯亚胺溶液。
7.按权利要求5所述的方法,其特征在于,所述步骤(3)中,还包括用稀盐酸降低溶液的pH值。
8.权利要求1所述的共价疏水修饰的聚乙烯亚胺在制备转染核酸的试剂中的应用。
9.按权利要求7所述的应用,其特征在于,所述核酸选自DNA或RNA。
10.按权利要求8所述的应用,其特征在于,所述DNA或RNA的形式为环形、线形或发卡结构。
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