CN111135306A - 基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法 - Google Patents
基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法 Download PDFInfo
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Abstract
本发明属于基因载体基础材料的合成技术领域,具体涉及一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法。利用叶酸靶向聚乙二醇修饰型超支化聚胺四氧化三铁纳米晶体以构筑叶酸和磁性双靶向型非病毒基因载体,能够赋予非病毒基因载体以叶酸和磁性双重靶向特性,从而实现载体对肿瘤等的主动靶向和磁靶向,可以用于基因治疗、磁热疗等领域。
Description
技术领域
本发明属于基因载体基础材料的合成技术领域,具体涉及一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法。
背景技术
超支化聚胺具有三维准球形结构和大量的胺基,是一类非常优异的非病毒基因载体。同时,它还是一类理想的纳米反应器,可用来合成量子点、金属纳米晶体和磁性氧化物纳米晶体。利用超支化聚胺原位制备磁性氧化铁纳米晶体,可得到一类磁性的非病毒基因载体。
经对现有技术的文献检索发现,目前利用超支化聚胺原位制备磁性非病毒基因载体已有一定的报道[Shi, Y.F.; Zhou, L.Z.; Wang, R.B.; Pang, Y.; Xiao, W.C.; Li,H.Q.; Su, Y.; Wang, X.L.; Zhu, B.S.; Zhu, X.Y.; Yan, D.Y. and Gu, H.C.Nanotechnology2010, 21, 115103.; Shi, Y.F.; Du, J. M.; Zhou, L. Z.; Li, X.T.; Zhou, Y. H.; Li, L. L.; Zhu, X. Y. J. Mater. Chem.2012, 22, 355-360.;Mykhaylyk, O.; Antequera, Y.S.; Vlaskou, D.; Plank, C. Nat. Protoc.2007, 2,2391-2411.] 在这些报道中,人们利用超支化聚乙烯亚胺及其超分子组装体制备原位制备磁性非病毒基因载体,但是目前尚未有利用叶酸靶向聚乙二醇修饰型超支化聚胺原位制备叶酸和磁性双靶向型非病毒基因载体的报道。利用叶酸靶向聚乙二醇修饰型超支化聚胺原位叶酸和磁性双靶向型非病毒基因载体,能够赋予非病毒基因载体以叶酸和磁性双重靶向特性,从而实现载体对肿瘤等的主动靶向和磁靶向,利于基因治疗。
发明内容
本发明的目的是提供一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法。
为实现上述目的,本发明采用的技术方案是:
一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法,包括以下步骤:
(1)将叶酸靶向聚乙二醇修饰型超支化聚胺溶解于水中,并通氩气除氧,得到叶酸靶向聚乙二醇修饰型超支化聚胺水溶液;
(2)氩气保护下,向步骤(1)得到的水溶液中加入七水硫酸亚铁的无氧水溶液,磁力搅拌1-6h,得到Fe(OH)2/叶酸靶向聚乙二醇修饰型超支化聚胺复合物水溶液;
(3)将步骤(2)所得的产物于90-130℃下微波加热0.5-2h,即可得到Fe3O4/叶酸靶向聚乙二醇修饰型超支化聚胺复合物;
(4)将步骤(3)所得的产物在2-8℃条件下透析3-5d,抽滤除去沉淀,冷冻干燥,即可得到所述叶酸和磁性双靶向型非病毒基因载体。
优选的,步骤(1)中所述叶酸靶向聚乙二醇修饰型超支化聚胺为叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺、叶酸靶向聚乙二醇修饰型超支化聚酰胺-胺或叶酸靶向聚乙二醇修饰型超支化聚丙烯亚胺。
优选的,步骤(1)中叶酸靶向聚乙二醇修饰型超支化聚胺是以叶酸、聚乙二醇和超支化聚胺作为原料制备得到的,其中超支化聚胺为超支化聚乙烯亚胺(HPEI)、超支化聚酰胺-胺(HPAMAM)或超支化聚丙烯亚胺(PPI)。
优选的,步骤(1)中叶酸靶向聚乙二醇修饰型超支化聚胺水溶液的浓度为2.5-200g/L,体积为10-100mL。
优选的,步骤(2)中所述七水硫酸亚铁水溶液的浓度为2-1500 g/L,体积为2-20mL。
优选的,步骤(3)中的微波功率为100-600W。
采用上述方法制备的叶酸和磁性双靶向型非病毒基因载体。
本发明产生的有益效果是:本发明利用叶酸靶向聚乙二醇修饰型超支化聚胺原位制备了叶酸和磁性双靶向型非病毒基因载体,该方法合成简单,避免了传统方法(先合成磁性纳米晶体再用超支化聚胺修饰)的繁琐过程,且制备的基因载体在转染过程中转染效率高于传统方法(先合成磁性纳米晶体再用超支化聚胺修饰)制备的非病毒基因载体。该方法实现了非病毒基因载体的叶酸和磁性双靶向特性,利于基因载体靶向至肿瘤等部位进行基因治疗。
附图说明
图1为本发明的合成过程示意图;
图2为实施例1基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的流体力学尺寸(a)和电位图(b);
图3为实施例1基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的透射电镜图;
图4为实施例1基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的饱和磁化强度图;
图5为实施例1基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的细胞毒性图;
图6为实施例1基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的基因转染效率图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。
实施例所使用的超支化聚乙烯亚胺(HPEI)购买自Sigma-Aldrich (M w=25000, 支化度=50%, PDI = 2.5)。实施例所使用的超支化聚酰胺-胺(HPAMAM)(M w = 3.8 × 103,PDI = 1.27)是根据参考文献[Shi, Y. F.; Lei, G.Y.;Zhou, L.Z.; Li, Y.Y.; Zhang,X.M.; Yang, Y.J.; Peng, H.; Peng, R.; Wang, H.C.; Cai, X.F.; Chen, X.L.;Wang, M.Y.; Wang, G. Polymers2019, 11, 1926.]合成的。
叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺和叶酸靶向聚乙二醇修饰型超支化聚酰胺-胺是根据参考文献[Cho, K.C.; Jeong, J.H.; Chung, H.J.; Joe, C. O.; Kim,S.W.; Park, T, G. Journal of Controlled Release2005, 108, 121.]合成的。合成的工艺过程是,利用NH2-PEG-COOH和活化的叶酸脱水反应,得到FA-PEG-COOH,随后将活化的FA-PEG-COOH和超支化聚乙烯亚胺或超支化聚酰胺-胺以不同的摩尔比反应,即可得到叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺或叶酸靶向聚乙二醇修饰型超支化聚酰胺-胺。
实施例1
一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法,具体包括以下步骤:
(1)在100mL反应瓶中加入1g叶酸(FA)靶向聚乙二醇(PEG)修饰型超支化聚乙烯亚胺(FA-PEG3.3-HPEI,即每个超支化聚乙烯亚胺(HPEI)分子平均接枝3.3个FA-PEG分子),再加入40mL超纯水,搅拌溶解,通氩气除氧,得到FA-PEG3.3-HPEI水溶液;
(2)取10mL浓度为100g/L的七水硫酸亚铁无氧水溶液(本实施例是在水溶液中通入氩气除氧来实现无氧条件的),在氩气保护下,加入到步骤(1)制备的FA-PEG3.3-HPEI水溶液中,磁力搅拌6h,得到Fe(OH)2/FA-PEG3.3-HPEI复合物水溶液;
(3)将步骤(2)制备的Fe(OH)2/FA-PEG3.3-HPEI复合物水溶液于100℃、200W功率下微波加热1h,得到Fe3O4/FA-PEG3.3-HPEI纳米复合物水溶液;
(4)将步骤(3)制备的Fe3O4/FA-PEG3.3-HPEI纳米复合物水溶液于5℃下透析(透析袋截留分子量:8000 Da)3d,抽滤除沉淀,冷冻干燥,即可得到基于叶酸靶向聚乙二醇修饰型超支化聚胺制备的叶酸和磁性双靶向型非病毒基因载体(Fe3O4/FA-PEG3.3-HPEI),该非病毒基因载体具有叶酸基团,可实现对肿瘤部位的主动结合和靶向,该非病毒基因载体同时含有磁性Fe3O4纳米晶体,能够在磁场作用下靶向至特定部位。
图1为本发明的合成过程示意图。本实施例所制备的基于叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺制备的叶酸和磁性双靶向型非病毒基因载体的流体力学尺寸如图2a所示,图2b为该非病毒基因载体的电位图,从图2a中可以看出流体力学尺寸为37.2纳米,图2b可以看出电位为+10.9 mV。
图3为实施例1制备的非病毒基因载体的透射电镜图,由图3可知,该非病毒基因载体中的Fe3O4纳米晶体具有球形和立方体结构,其尺寸约为16纳米。
图4为实施例1制备的非病毒基因载体的饱和磁化强度图,从图3中可以看出其饱和磁化强度为66.0 emu/gFe。
图5为不同浓度下实施例1制备的非病毒基因载体与HPEI和FA-PEG3.3-HPEI的细胞毒性图,其中该非病毒基因载体与HPEI和FA-PEG3.3-HPEI的浓度分别设置1μg/mL、5μg/mL、10μg/mL、15μg/mL、20μg/mL、50μg/mL、100μg/mL,从图4中可以看出所述非病毒基因载体的细胞活性与HPEI和FA-PEG3.3-HPEI相比都有一定程度的提高,但是随着浓度的提高非病毒基因载体与HPEI和FA-PEG3.3-HPEI的细胞毒性均呈现下降趋势。
图6为实施例1制备的非病毒基因载体的基因转染效率图,由图5可知,在不同的Fe/DNA质量比下,该非病毒基因载体的荧光素酶表达量最高分别是HPEI基因载体转染和FA-PEG3.3-HPEI基因载体转染的21倍和14倍。
实施例2
一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法,具体包括以下步骤:
(1)在100mL反应瓶中加入1g叶酸(FA)靶向聚乙二醇(PEG)修饰型超支化聚乙烯亚胺(FA-PEG5.9-HPEI,即每个超支化聚乙烯亚胺(HPEI)分子平均接枝5.9个FA-PEG分子),再加入40mL超纯水,搅拌溶解,通氩气除氧,得到FA-PEG5.9-HPEI水溶液;
(2)取10mL浓度为100 g/L的七水硫酸亚铁无氧水溶液(本实施例是在水溶液中通入氩气除氧来实现无氧条件的),在氩气保护下,加入到步骤(1)制备的FA-PEG5.9-HPEI水溶液中,磁力搅拌6 h,得到Fe(OH)2/FA-PEG5.9-HPEI复合物水溶液;
(3)将步骤(2)制备的Fe(OH)2/FA-PEG5.9-HPEI复合物水溶液于100℃、200W功率下微波加热1h,得到Fe3O4/FA-PEG5.9-HPEI纳米复合物水溶液;
(4)将步骤(3)制备的Fe3O4/FA-PEG5.9-HPEI纳米复合物水溶液于5℃下透析(透析袋截留分子量:8000 Da)3 d,抽滤除沉淀,冷冻干燥,即可得到基于叶酸靶向聚乙二醇修饰型超支化聚胺制备的叶酸和磁性双靶向型非病毒基因载体(Fe3O4/FA-PEG5.9-HPEI)。
实施例3
一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法,具体包括以下步骤:
(1)在100mL反应瓶中加入1g叶酸(FA)靶向聚乙二醇(PEG)修饰型超支化聚酰胺-胺(FA-PEG-HPAMAM,即每个超支化聚酰胺-胺(HPAMAM)分子平均接枝1个FA-PEG分子),再加入40mL超纯水,搅拌溶解,通氩气除氧,得到FA-PEG-HPAMAM水溶液;
(2)取10mL浓度为100 g/L的七水硫酸亚铁无氧水溶液(本实施例是在水溶液中通入氩气除氧来实现无氧条件的),在氩气保护下,加入到步骤(1)制备的FA-PEG-HPAMAM水溶液中,磁力搅拌6h,得到Fe(OH)2/ FA-PEG-HPAMAM复合物水溶液;
(3)将步骤(2)制备的Fe(OH)2/FA-PEG-HPAMAM复合物水溶液于100℃、200W功率下微波加热1h,得到Fe3O4/FA-PEG-HPAMAM纳米复合物水溶液;
(4)将步骤(3)制备的Fe3O4/FA-PEG-HPAMAM纳米复合物水溶液于5℃下透析(透析袋截留分子量:8000 Da)3 d,抽滤除沉淀,冷冻干燥,即可得到基于叶酸靶向聚乙二醇修饰型超支化聚酰胺-胺制备的叶酸和磁性双靶向型非病毒基因载体(Fe3O4/FA-PEG-HPAMAM)。
实施例2-3制备的叶酸和磁性双靶向型非病毒基因载体和实施例1的非病毒基因载体均具有较高的转染效率,同时还具有叶酸和磁性双靶向特性,其能够靶向至肿瘤部位进行基因治疗。
尽管已用具体实施例来说明和描述了本发明,然而应意识到,在不背离本发明的精神和范围的情况下可以作出许多其它的更改和修改。因此,这意味着在所附权利要求中包括属于本发明范围内的所有这些变化和修改。
Claims (7)
1.一种基于叶酸靶向聚乙二醇修饰型超支化聚胺制备叶酸和磁性双靶向型非病毒基因载体的方法,其特征在于,包括以下步骤:
(1)将叶酸靶向聚乙二醇修饰型超支化聚胺溶解于水中,并通氩气除氧,得到叶酸靶向聚乙二醇修饰型超支化聚胺水溶液;
(2)氩气保护下,向步骤(1)得到的水溶液中加入七水硫酸亚铁的无氧水溶液,磁力搅拌1-6h,得到Fe(OH)2/叶酸靶向聚乙二醇修饰型超支化聚胺复合物水溶液;
(3)将步骤(2)所得的产物于90-130℃下微波加热0.5-2h,即可得到Fe3O4/叶酸靶向聚乙二醇修饰型超支化聚胺复合物;
(4)将步骤(3)所得的产物在2-8℃条件下透析3-5d,抽滤除去沉淀,冷冻干燥,即可得到所述叶酸和磁性双靶向型非病毒基因载体。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述叶酸靶向聚乙二醇修饰型超支化聚胺为叶酸靶向聚乙二醇修饰型超支化聚乙烯亚胺、叶酸靶向聚乙二醇修饰型超支化聚酰胺-胺或叶酸靶向聚乙二醇修饰型超支化聚丙烯亚胺。
3.根据权利要求1所述的制备方法,其特征在于,步骤(1)中叶酸靶向聚乙二醇修饰型超支化聚胺是以叶酸、聚乙二醇和超支化聚胺作为原料制备得到的,其中超支化聚胺为超支化聚乙烯亚胺、超支化聚酰胺-胺或超支化聚丙烯亚胺。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中叶酸靶向聚乙二醇修饰型超支化聚胺水溶液的浓度为2.5-200g/L,体积为10-100mL。
5.根据权利要求1所述的制备方法,其特征在于,步骤(2)中所述七水硫酸亚铁水溶液的浓度为2-1500g/L,体积为2-20mL。
6.根据权利要求1所述的制备方法,其特征在于,步骤(3)中的微波功率为100-600W。
7.采用权利要求1-6方法制备的叶酸和磁性双靶向型非病毒基因载体。
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