CN101062417A - 一种用壳聚糖修饰脂质体制备基因给药载体的方法 - Google Patents
一种用壳聚糖修饰脂质体制备基因给药载体的方法 Download PDFInfo
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Abstract
本发明提供一种用壳聚糖修饰脂质体制备基因给药载体的方法,以磷脂和胆固醇组成膜材,采用逆向蒸发法或薄膜分散法,并经过探头超声和挤压过膜,得到脂质体溶液,配制不同分子量的壳聚糖溶液,将壳聚糖溶液与脂质体溶液进行孵育,制备获得壳聚糖修饰的脂质体。本发明结合壳聚糖的正电荷、低毒性和脂质体的细胞相容性,获得壳聚糖修饰的脂质体,可作为基因给药载体。现有的脂质体作为基因载体往往在血清存在条件下转染效率较低,而阳离子脂质体通常有较大的细胞毒性。本发明在体外血清存在情况下具有良好的稳定性,细胞毒性小于阳离子脂质体。本发明方法设计合理,制备工艺简单,体外稳定性好,具有很好的体内应用前景。
Description
技术领域
本发明属基因给药载体的制备方法,涉及一种用壳聚糖修饰脂质体的制备方法,经修饰的脂质体可作为基因给药载体。
背景技术
随着人类基因组计划的完成,人们对疾病的遗传学物质基础有了更深的了解,基因治疗(gene therapy)成为了一种很有前途的治疗手段,被认为是治疗遗传性先天疾病、恶性肿瘤、传染病等最有希望的治疗方案之一。
基因治疗是指将目的基因用基因转移技术导入靶细胞,使其表达此基因而获得特定的功能,从而达到治疗之目的,而基因治疗面临的首要技术问题是基因载体的构建。脂质体是具有双层膜的封闭式粒子,作为基因载体主要是利用脂质体能够促进极性大分子穿透细胞膜的原理。脂质体介导DNA进入细胞的研究已有约20年的历史,由于阳离子脂质体具有较高的转染效率,其在基因治疗的研究中应用更为普遍。但有文献报道,在提高阳离子脂质体转染活性的同时,其表面的正电荷导致相应的细胞毒性。而阴性脂质体和中性脂质体与细胞的结合相对较差,这些限制了脂质体在基因治疗中的应用。与此同时,脂质体还存在稳定性较差,易出现絮凝,粒径变大等现象。
壳聚糖属天然高分子多糖,表面带正电荷,可通过电荷之间的相互作用,与DNA形成稳定的多聚复合物,使得DNA不易被核酸酶降解,并可以与带负电荷的细胞表面相结合,从而被有效地摄取,并介导基因的转移。壳聚糖的细胞毒性小,但单独使用壳聚糖作为基因载体,其转染效率要低于脂质体载体。
发明内容
本发明的目的是提供一种用壳聚糖修饰脂质体制备基因给药载体的方法,通过以下步骤实现:以磷脂和胆固醇组成膜材,磷脂和胆固醇分别为所有常用的磷脂类和胆固醇类,组成比例为磷脂10~200mg,胆固醇5~100mg,蒸馏水2.5~50mL,氯仿7.5~150mL。用逆向蒸发法或薄膜分散法,并经过探头超声和挤压过膜,探头超声为100~500W,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜的孔径为0.1~0.22μm,得到脂质体溶液,配制不同分子量(50KDa~1000KDa)的壳聚糖溶液,修饰脂质体的壳聚糖分子量为50kDa~1000kDa,溶剂为0.1%~1%的冰醋酸,壳聚糖浓度为0.2%~1.0%,将壳聚糖溶液与脂质体溶液进行孵育后制得,孵育方法为:将脂质体溶液缓慢滴加到壳聚糖溶液中,滴加时间为1~10分钟,室温搅拌时间为0.5~2小时,制备获得壳聚糖修饰的脂质体。
壳聚糖分子量繁多,其他种类的壳聚糖也适用与本发明的脂质体修饰。
经壳聚糖修饰的脂质体制剂在制备基因给药载体中应用。
本发明的有益之处是:本发明结合壳聚糖的正电荷、低毒性和脂质体的细胞相容性,提供一种新型的壳聚糖修饰脂质体制剂作为基因给药载体。现有的脂质体制剂作为基因载体往往在血清存在条件下转染效率较低,而阳离子脂质体通常有较大的细胞毒性。本发明所制备的制剂在体外血清存在情况下具有良好的稳定性,细胞毒性小于阳离子脂质体。本发明方法设计合理,制备工艺简单,体外稳定性好,具有很好的体内应用前景。
附图说明
图1为本发明的透射电镜照片
图2为本发明在血清条件下的浊度变化
图3为本发明的细胞毒性
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例1 取大豆磷脂10~200mg,胆固醇5~100mg溶于7.5~150mL氯仿,加入2.5~50mL蒸馏水,用逆向蒸发法制备脂质体。具体为:旋涡振荡10~30分钟,使之成乳,在旋转蒸发仪上真空旋转蒸发除去氯仿,得到脂质体的混悬液。脂质体溶液用100~500W探头超声处理,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜,孔径为0.1~0.22μm。取分子量450kDa的壳聚糖,溶于浓度0.1%~1%的冰醋酸,最终壳聚糖溶液浓度为0.2%~1.0%。将脂质体溶液缓慢注入壳聚糖溶液中,注入时间为1~10分钟,之后搅拌0.5~2小时得到壳聚糖修饰脂质体。
实施例2 取卵磷脂10~200mg,胆固醇5~100mg溶于7.5~150mL氯仿,加入2.5~50mL蒸馏水,用逆向蒸发法制备脂质体。脂质体溶液用100~500W探头超声处理,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜,孔径为0.1~0.22μm。取分子量900kDa的壳聚糖,溶于浓度0.1%~1%的冰醋酸,最终壳聚糖溶液浓度为0.2%~1.0%。将脂质体溶液缓慢注入壳聚糖溶液中,注入时间为1~10分钟,之后搅拌0.5~2小时得到壳聚糖修饰脂质体。
按薄膜分散法制备。具体为:取大豆磷脂10~200mg,胆固醇5~100mg溶于7.5~150mL氯仿,置于梨形瓶。旋转蒸发除去氯仿,形成脂质薄膜后,加入2.5~50mL蒸馏水超声水合。脂质体溶液用100~500W探头超声处理,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜,孔径为0.1~0.22μm。取分子量100kDa的壳聚糖,溶于浓度0.1%~1%的冰醋酸,最终壳聚糖溶液浓度为0.2%~1.0%。将脂质体溶液缓慢注入壳聚糖溶液中,注入时间为1~10分钟,之后搅拌0.5~2小时得到壳聚糖修饰脂质体。
实施例4 取卵磷脂10~200mg,胆固醇5~100mg溶于7.5~150mL氯仿,按上述薄膜分散法制备,加入2.5~50mL蒸馏水超声水合。脂质体溶液用100~500W探头超声处理,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜,孔径为0.1~0.22μm。取分子量900kDa的壳聚糖,溶于浓度0.1%~1%的冰醋酸,最终壳聚糖溶液浓度为0.2%~1.0%。将脂质体溶液缓慢注入壳聚糖溶液中,注入时间为1~10分钟,之后搅拌0.5~2小时得到壳聚糖修饰脂质体。
实施例5 取氢化磷脂10~200mg,胆固醇5~100mg溶于7.5~150mL氯仿,加入2.5~50mL蒸馏水,用逆向蒸发法制备脂质体。脂质体溶液用100~500W探头超声处理,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜,孔径为0.1~0.22μm。取分子量450kDa的壳聚糖,溶于浓度0.1%~1%的冰醋酸,最终壳聚糖溶液浓度为0.2%~1.0%。将脂质体溶液缓慢注入壳聚糖溶液中,注入时间为1~10分钟,之后搅拌0.5~2小时得到壳聚糖修饰脂质体。
表1空白脂质体和不同分子量壳聚糖修饰脂质体的粒径和电位(n=3)
粒径(nm) | 电位(mV) | |
空白脂质体壳聚糖修饰脂质体(450kDa;脂质体∶壳聚糖=0.5v/v)壳聚糖修饰脂质体(450kDa;脂质体∶壳聚糖=1.0v/v)壳聚糖修饰脂质体(900kDa;脂质体∶壳聚糖=0.5v/v)壳聚糖修饰脂质体(900kDa;脂质体∶壳聚糖=1.0v/v) | 184.6±22421.8±53506.1±75470.9±671134.8±230 | -1.9±0.444.1±1.241.1±1.340.5±1.543.8±2.6 |
实施例6 本发明的测定与实验如下:
1.壳聚糖修饰脂质体的形态观察
取适量壳聚糖修饰脂质体加适量的双蒸水稀释后,加至专用铜网上,0.2%磷钨酸染色,在透射电子显微镜下观察粒子的大小和形态(参见附图1)。
2.壳聚糖修饰脂质体的粒径和电位
一定量的壳聚糖修饰脂质体,用PBS稀释至适当浓度,激光粒度测定仪测定脂质体的粒径分布和表面电位(参见表1)。
3.体外血清存在情况下壳聚糖修饰脂质体的稳定性考察
壳聚糖修饰脂质体中加入血清,使最终血清浓度为10%。将其置于37℃恒温水浴中,分别于不同时间点,600nm处测定其吸光度,通过吸光度的变化,考察脂质体的稳定性,参见附图2,其中的ΔA为相对吸光度,T为时间。
4.壳聚糖修饰脂质体的细胞毒性实验
HeLa细胞(1×104个/孔)接种于96孔培养板,过夜培养至细胞完全贴壁,融合度为60~80%。PBS洗涤后加入无血清培养液100μl/孔,并加入不同量的壳聚糖修饰脂质体,空白对照组加100μl无血清培养液。孵箱中培养4h之后移去培养液,换成含10%小牛血清的完全培养基,继续培养24h。每孔加入20μlMTT(5mg/ml),4h后吸去培养液,加入150μl DMSO每孔,振摇10min,在酶标仪上,于570nm测定A值。按以下公式计算细胞生存率。
细胞生存率(%)=(Asample/Acontrol)×100%
结果表明壳聚糖修饰脂质体的细胞毒性小于阳离子脂质体,与空白脂质体相似(参见附图3)。
Claims (5)
1.一种用壳聚糖修饰脂质体制备基因给药载体的方法,其特征是通过以下步骤实现:脂质体的膜材由磷脂和胆固醇组成,组成比例为磷脂10~200mg,胆固醇5~100mg,蒸馏水2.5~50mL,氯仿7.5~150mL,用逆向蒸发法或薄膜分散法,并经过探头超声和挤压过膜,探头超声为100~500W,工作时间1~3秒,间隙时间2~4秒,循环时间为30~240次,超声条件为冰浴,挤压过膜的孔径为0.1~0.22μm,得到脂质体溶液,配制50KDa~1000KDa分子量的壳聚糖溶液,将壳聚糖溶液与脂质体溶液进行孵育,获得壳聚糖修饰的脂质体。
2.根据权利要求书1所述的一种用壳聚糖修饰脂质体制备基因给药载体的方法,其特征是:其中配制的壳聚糖溶液所用的壳聚糖分子量为50kDa~1000kDa,溶剂为0.1%~1%的冰醋酸,壳聚糖浓度为0.2%~1.0%。
3.根据权利要求书1所述的一种用壳聚糖修饰脂质体制备基因给药载体的方法,其特征是:所述的孵育方法是将脂质体溶液缓慢滴加到壳聚糖溶液中,滴加时间为1~10分钟,室温搅拌时间为0.5~2小时。
4.根据权利要求书3所述的一种用壳聚糖修饰脂质体制备基因给药载体的方法,其特征是:脂质体溶液和壳聚糖溶液的体积比为0.1~1.25。
5.根据权利要求书1所述的一种用壳聚糖修饰的脂质体在制备基因给药载体中的应用。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101703783B (zh) * | 2009-11-30 | 2011-09-28 | 浙江大学 | 一种糖皮质激素接枝的基因给药载体的制备方法 |
CN102978233A (zh) * | 2012-11-16 | 2013-03-20 | 河南农业大学 | 一种黑根霉菌丝脂质体直接转化方法 |
CN105232466A (zh) * | 2015-10-16 | 2016-01-13 | 上海纳米技术及应用国家工程研究中心有限公司 | 一种用于重金属离子吸附的纳米颗粒的制备方法 |
CN107903341A (zh) * | 2017-07-27 | 2018-04-13 | 大连民族大学 | 双脂肪链取代基磷脂酰乙醇胺壳聚糖的应用 |
CN111012920A (zh) * | 2019-12-17 | 2020-04-17 | 佛山科学技术学院 | 玉屏风多糖脂质体及其制备方法 |
CN111228243A (zh) * | 2019-12-24 | 2020-06-05 | 珠海亿胜生物制药有限公司 | 一种雾化吸入用妥布霉素脂质体及其制备方法 |
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CN101703783B (zh) * | 2009-11-30 | 2011-09-28 | 浙江大学 | 一种糖皮质激素接枝的基因给药载体的制备方法 |
CN102978233A (zh) * | 2012-11-16 | 2013-03-20 | 河南农业大学 | 一种黑根霉菌丝脂质体直接转化方法 |
CN105232466A (zh) * | 2015-10-16 | 2016-01-13 | 上海纳米技术及应用国家工程研究中心有限公司 | 一种用于重金属离子吸附的纳米颗粒的制备方法 |
CN105232466B (zh) * | 2015-10-16 | 2018-05-11 | 上海纳米技术及应用国家工程研究中心有限公司 | 一种用于重金属离子吸附的纳米颗粒的制备方法 |
CN107903341A (zh) * | 2017-07-27 | 2018-04-13 | 大连民族大学 | 双脂肪链取代基磷脂酰乙醇胺壳聚糖的应用 |
CN111012920A (zh) * | 2019-12-17 | 2020-04-17 | 佛山科学技术学院 | 玉屏风多糖脂质体及其制备方法 |
CN111228243A (zh) * | 2019-12-24 | 2020-06-05 | 珠海亿胜生物制药有限公司 | 一种雾化吸入用妥布霉素脂质体及其制备方法 |
CN111228243B (zh) * | 2019-12-24 | 2022-02-18 | 珠海亿胜生物制药有限公司 | 一种雾化吸入用妥布霉素脂质体及其制备方法 |
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