CN104174034A - 肝星状细胞靶向的基因药物输送载体及其制备方法和应用 - Google Patents
肝星状细胞靶向的基因药物输送载体及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物输送技术领域。具体涉及一种肝星状细胞靶向的基因药物输送载体及其制备方法和应用。该方法通过将视黄醇分子偶联到聚乙烯亚胺载体上,利用其对肝星状细胞的主动靶向功能,用作肝纤维化和肝硬化治疗的基因药物输送载体。载体中阳离子材料聚乙烯亚胺通过非共价的静电作用包裹基因药物,使药物更容易释放出来,载体中的视黄醇赋予载体肝星状细胞靶向特性,提高了药物的利用率,降低了其毒副作用,载体进入血液循环后可结合白蛋白,从而延长载体的循环时间。为肝纤维化和肝硬化等常见的慢性进行性肝脏疾病提供了一种新的有效的抗肝纤维化和肝硬化的基因药物靶向输送载体。
Description
一、技术领域
本发明属于药物输送技术领域。具体涉及一种肝星状细胞靶向的基因药物输送载体及其制备方法和应用。
二、背景技术
肝纤维化和肝硬化是常见的慢性进行性肝脏疾病,是肝脏对慢性损伤进行的一种修复反应。受损的肝细胞和活化的枯否氏细胞分泌的各种细胞因子会导致肝星状细胞(HSC)活化成为肌纤维母细胞,活化的星状细胞合成并分泌大量的以胶原为主的细胞外基质沉积在肝脏,导致肝纤维化的产生,肝纤维化可进一步发展成为肝硬化。
随着对肝纤维化和肝硬化发病分子机理认识的深入及基因治疗技术的发展,使基因治疗肝纤维化和肝硬化成为可能。目前基因治疗主要集中于调控肝纤维化和肝硬化进程中起主要作用的肝星状细胞(HSC)活化相关的细胞因子的表达。报告较多的有转化生长因子β(TGF-β)肝细胞生长因子(HGF)及干扰素γ(IFN-γ)等。但是由于药物进入肝脏后主要被肝细胞或枯否氏细胞吸收,而在肝内细胞群体中所占比例较小的肝星状细胞(HSC)药物吸收困难,导致治疗效果并不理想。
针对上述问题,靶向输送成为肝纤维化和肝硬化治疗研究中非常有前途的治疗策略。药物靶向载体能够选择性地分布于肝脏,并能高特异性、高亲和力地与肝星状细胞(HSC)结合,将药物特异性释放至肝星状细胞(HSC)而发挥抗肝纤维化和肝硬化作用,同时减少因药物在其他脏器中分布而引起的不良反应。但常用载体存在血液循环时间短,药物释放困难等问题,目前尚缺少一种有效的抗肝纤维化和肝硬化的基因药物靶向输送载体。
三、发明内容
本发明需要解决的问题是提供一种具有肝星状细胞靶向功能的基因输送载体及其制备方法和该载体能够用于肝纤维化和肝硬化治疗基因药物的靶向输送。
本发明的技术方案为将肝星状细胞靶向配体偶联到阳离子载体上。所用的靶向配体是视黄醇(Retinol)分子;所述的阳离子载体是聚乙烯亚胺(PEI)。
为了更好的实现本发明,发明人提供以下优选方案:
所述偶联过程为:取0.56g N,N-羰基二咪唑(CDI)溶于20ml二甲基亚砜(DMSO)中,完全溶解后加入1g视黄醇,在避光条件下30℃恒温搅拌24小时;再加入4.32g聚乙烯亚胺(PEI),继续搅拌24小时;将上述溶液转入截留分子量为12000-14000的透析袋中,双蒸水透析4天;将透析液冻干得到药物输送载体材料。
所述聚乙烯亚胺(PEI)优选以下几种:线型PEI,分子量为1,300道尔顿,2,500道尔顿,4,000道尔顿,25,000道尔顿,40,000道尔顿,250,000道尔顿;支化PEI,分子量为600道尔顿,1,200道尔顿,1,800道尔顿,10,000道尔顿,25,000道尔顿,70,000道尔顿,50,000-100,000道尔顿,800,000道尔顿。
相对于现有输送载体,本发明的有益效果是:
载体中阳离子材料聚乙烯亚胺通过非共价的静电作用包裹基因药物,使药物更容易释放出来,载体中的视黄醇赋予载体肝星状细胞靶向特性,提高了药物的利用率,降低了其毒副作用,载体进入血液循环后可结合白蛋白,从而延长载体的循环时间。为肝纤维化和肝硬化等常见的慢性进行性肝脏疾病提供了一种新的有效的抗肝纤维化和肝硬化的基因药物靶向输送载体。
四、附图说明
图1是视黄醇(Retinol)与聚乙烯亚胺(PEI)偶联过程图及Retinol-c-PEI(RcP)结构图
图2是PEI和RcP的傅里叶变换红外光谱检测图谱
图3是Rho-ASO/PEI和Rho-ASO/RcP转染肝星状细胞(HSC-T6)的情况
图4是qPCR测定四氯化碳诱导的小鼠肝纤维化模型中对照组、模型组和治疗组的I型胶原蛋白mRNA的相对表达量
图5是qPCR测定四氯化碳诱导的小鼠肝硬化模型中对照组、模型组和治疗组的I型胶原蛋白mRNA的相对表达量
五、具体实施方式
本发明主要涉及肝星状细胞靶向输送载体的制备方法及其应用。在具体实施过程中,涉及载体的制备,载体对肝星状细胞的转染以及载体用于肝纤维化和肝硬化的治疗。
1.载体的制备
①视黄醇的活化
取0.56g N,N-羰基二咪唑(CDI)溶于20ml二甲基亚砜(DMSO)中,完全溶解后加入1g视黄醇,在避光条件下30℃恒温搅拌24小时,得到活化的视黄醇。
②聚乙烯亚胺和活化的视黄醇偶联
在活化的视黄醇中加入4.32g聚乙烯亚胺(PEI),继续搅拌24小时,得到RcP。聚乙烯亚胺分子量如下:线型PEI,分子量为1,300道尔顿,2,500道尔顿,4,000道尔顿,25,000道尔顿,40,000道尔顿,250,000道尔顿;支化PEI,分子量为600道尔顿,1,200道尔顿,1,800道尔顿,10,000道尔顿,25,000道尔顿,70,000道尔顿,50,000-100,000道尔顿,800,000道尔顿。
③透析
将反应液转入截留分子量为12000-14000道尔顿的透析袋中,双蒸水透析4天。
④冻干
将透析液放到-80℃超低温冰箱2-3小时,在冷冻干燥机上冷冻干燥48小时。然后将材料保存于干燥器中备用。
图2是PEI和RcP傅里叶变换红外光谱检测图谱,从图中可以看出,1745.2cm-1处的吸收峰是羧基和氨基反应的信号,而在3284.2cm-1处吸收峰的显著变化则表明PEI的–NH2基与Retinol连接。在1648.8cm-1和1164.8cm-1处的峰值的变化则表明PEI上伯氨基和叔氨基也已经被修饰。以上说明视黄醇分子被成功的偶联到聚乙烯亚胺分子上,RcP载体制备成功。
2.ASO/RcP转染肝星状细胞
①铺板
将大鼠肝星状细胞(HSC-T6)消化成单细胞悬液,稀释到1×105/ml的密度加入24孔板内,每孔0.5ml。放在37℃培养箱培养24小时。
②载体-核酸复合物的制备
配制浓度均为0.25mg/ml的罗丹明修饰I型胶原蛋白的反义核酸(Rho-ASO),PEI和RcP溶液。将Rho-ASO分别和PEI,RcP等体积混合,漩涡振荡5分钟,室温静置20分钟,得到Rho-ASO/PEI和Rho-ASO/RcP复合物。
③转染
将HSC-T6原培养液换为含有视黄醇结合蛋白(RBP)的opti-MEM培养液,再分别加入Rho-ASO/PEI和Rho-ASO/RcP两种复合物。放在37℃培养箱培养。
④荧光显微镜观察
转染4-6小时后,将细胞用1×PBS清洗2次→4%多聚甲醛固定15分钟→1×PBS清洗3次→DAPI染细胞核5分钟→1×PBS清洗2次。置于荧光显微镜下使用561nm激发光观察细胞转染情况。
结果表明(图3),和PEI相比,RcP对肝星状细胞有较高的转染效率。
3.ASO/RcP用于四氯化碳诱导的小鼠肝纤维化模型的治疗
配制含25%四氯化碳(CCl4)的橄榄油溶液。将4-6周龄ICR雄性小鼠随机分为三组,每组6只。模型组按4μl/g体重腹腔注射CCl4溶液,对照组小鼠按体重注射相同体积的橄榄油。每周两次,持续注射4周。对于治疗组小鼠,在造模的同时通过尾静脉注射ASO/RcP复合物,每周一次,每次100μl。
结果表明(图4),和对照组相比,模型组I型胶原蛋白mRNA相对表达量显著升高(*:P<0.01),说明四氯化碳诱导的小鼠肝纤维化模型造模成功;和模型组相比,治疗组I型胶原蛋白mRNA相对表达量显著降低(#:P<0.01),说明ASO/RcP对肝纤维化有很好的治疗效果。
4.ASO/RcP用于四氯化碳诱导的小鼠肝硬化模型的治疗
配制含25%四氯化碳(CCl4)的橄榄油溶液。将4-6周龄ICR雄性小鼠随机分为三组,每组6只。模型组按4μl/g体重腹腔注射CCl4溶液,对照组小鼠按体重注射相同体积的橄榄油。每周两次,持续注射10周。对于治疗组小鼠,在造模的同时通过尾静脉注射ASO/RcP复合物,每周一次,每次100μl。
结果表明(图5),和对照组相比,模型组I型胶原蛋白mRNA相对表达量显著升高(*:P<0.001),说明四氯化碳诱导的小鼠肝硬化模型造模成功;和模型组相比,治疗组I型胶原蛋白mRNA相对表达量显著降低(#:P<0.001),说明ASO/RcP对肝硬化有很好的治疗效果。
Claims (5)
1.一种肝星状细胞靶向的基因药物输送载体,其特征是:将肝星状细胞靶向配体偶联到阳离子载体上,所述靶向配体是视黄醇(Retinol)分子,所述阳离子载体是聚乙烯亚胺(PEI)。
2.根据权利要求1所述的肝星状细胞靶向的基因药物输送载体,其特征在于:聚乙烯亚胺(PEI)是线型的或支化的,是各种分子量的聚乙烯亚胺(PEI):从小于600道尔顿到大于800,000道尔顿。
3.根据权利要求1所述的肝星状细胞靶向的基因药物输送载体,其特征在于:视黄醇(Retinol)和聚乙烯亚胺(PEI)的质量比为1:0.5-1:20。
4.根据权利要求1所述的肝星状细胞靶向的基因药物输送载体的制备方法,其特征在于由以下步骤构成:
(1).取0.56g N,N-羰基二咪唑(CDI)溶于20ml二甲基亚砜(DMSO)中,完全溶解后加入1g视黄醇,在避光条件下30℃恒温搅拌24小时;
(2).再加入4.32g聚乙烯亚胺(PEI),继续搅拌24小时;
(3).将上述溶液转入截留分子量为12000-14000的透析袋中,双蒸水透析4天;
(4).将透析液放到-80℃超低温冰箱2-3小时,在冷冻干燥机上冷冻干燥48小时后得到药物输送载体材料。
5.权利要求1所述的肝星状细胞靶向的基因药物输送载体在基因药物治疗肝纤维化或肝硬化中的应用。
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CN111407899A (zh) * | 2020-02-21 | 2020-07-14 | 哈尔滨医科大学 | 一种可以评估肝脏纤维化程度的肝星状细胞靶向磁共振分子显像剂及其制备方法 |
CN115624539A (zh) * | 2022-12-16 | 2023-01-20 | 首都医科大学附属北京朝阳医院 | 一种脂质纳米颗粒及其制备方法和应用 |
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