CN109512784A - 一种磁性靶向制剂的制备 - Google Patents
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Abstract
本发明涉及一种磁性靶向制剂的制备。主要制备方法是:以带‑NH2的磁性微球为具有导向作用的磁核,以改性后在水溶液中可自组装形成胶束的海藻酸钠为药物载体骨架材料,以阿霉素为包裹在胶束内部的疏水性药物。通过化学反应得到磁靶向制剂,以实现磁靶向药物载体在细胞免疫等方面的后续应用。该方法的主要特点是:磁靶向药物载体具有靶向性、实验操作简单、无毒副作用、可使水溶液中载药胶束与疏水性药物分开等。
Description
技术领域
本发明涉及分析和医学领域,将改性后的,在水溶液中可自组装形成胶束的疏水改性海藻酸钠(HM-alginate)作为疏水性药物载体,使其与带有-NH2基团的磁性微球相接,通过磁性分离,使水溶液中的载药胶束与疏水性药物分离从而制备磁性靶向制剂。具体涉及了一种磁性靶向药物载体的制备。
背景技术
磁性靶向药物之所以能够应用于靶向治疗,主要是通过磁性靶向给药系统对病变部位进行治疗。将磁靶向药物用于磁靶向给药系统的基本原理是:将磁性载药粒子注射到体内,在外部加以磁场,通过外加磁场的诱导性以及磁性粒子在体内的流动性,能够将磁性载药微粒逐渐转移到病变区,然后载药微粒以特定的受控方式(酶的活性或者其他生理条件的改变,例如pH值、温度改变或者渗透压等)进行缓慢释放,在病变区集中并发挥药物的作用。在本质上,磁靶向制剂的靶向过程是体内血流对载药微粒的推动作用以及外加磁场对磁性载药微粒的磁力综合作用的结果。磁靶向药物具有使用简便、具有靶向性、可增加病变部位药物浓度、提高药物疗效等优点(Wei T,Liu J,Ma H,et al.Nano Lett.2013,13:2528-2534),在生物医学领域有着重要的应用。
磁靶向给药系统也叫做磁靶向制剂,主要由以下三部分组成:一、有较好导向作用的磁性物质,二、有良好生物相容性、生物可降解性的药物载体骨架,三、能包裹于载体内部的药物(Lee J H,Kim K Y,Jin H,et al.ACS Appl.Mater.Interfaces 2018,10:3380-3391)。磁性物质可以使用带有-NH2磁性微球,药物用阿霉素(Dox),将具有两亲性能,生物相容性好的HM-alginate作为载体骨架材料。由这三部分组成磁靶向制剂,应用于免疫分析方面。
现如今已经开发出许多高分子材料做为药物载体(Ulbrich K,HoláK,V,etal.Chem.Rev.2016,116:5338-5431)。海藻酸钠是水溶性很好的高分子材料,具有良好的生物相容性,在某些疾病的治疗方面发挥了重大作用。但是其亲水性能太强,导致一些疏水性药物无法负载,所以对海藻酸钠进行疏水改性后即可装载疏水性的药物(Pourjavadi A,Amin S S,Hosseini S H.Ind.Eng.Chem.Res.2018,57:822-832)。通过包埋作用,两亲性的聚合物能够提高难溶性药物的溶解能力和生物利用度。HM-alginate在水溶液中组成的胶束能够包合疏水性分子,从而能够达到屏蔽、保护、控制释放疏水性药物的目的。因此,关于两亲性海藻酸钠的制备及其在医药领域应用的研究受到越来越多的关注。
发明内容
本发明提供了一种磁性靶向制剂的制备方法。先对天然高分子长链海藻酸钠进行疏水改性,得到两亲性的HM-alginate,将HM-alginate作为疏水药物Dox的载体,然后将载药后的HM-alginate与磁性微球上的-NH2相结合,通过活化活性基团来达到制备磁靶向制剂的目的。
技术方案
在水溶液中,将载药胶束与磁性微球相结合,通过磁性分离不仅能够达到使载药胶束与游离的疏水性药物分离的效果而且能制备一种磁性靶向制剂。具体实验步骤如下:
(1)疏水改性海藻酸钠的制备:准确称取5.0g海藻酸钠,加入70mL去离子水,机械搅拌后得到黄色均匀的乳状液。用氢氧化钠溶液(0.2mol/L)将溶液pH调节至9.0左右,缓慢滴加十二烷基缩水甘油醚(DGE)和十二烷基硫酸钠(SDS)各3mL,水浴加热至75℃后,回流反应8h。反应完成后冷却至室温,将混合液的pH用乙酸(1:1)调至4左右。用丙酮浸泡以除去混合物中的水、未反应的DGE和SDS,将析出后的产物进行过滤,再用丙酮浸泡12h。过滤后,将得到的淡黄色纤维状固体置于真空恒温干燥箱中干燥24h,干燥温度为60℃。
(2)载药胶束的制备:准确称取干燥后的疏水改性海藻酸钠0.2g,配置浓度为20mg/mL的疏水改性海藻酸钠胶束溶液。搅拌均匀后加入2mg阿霉素,搅拌24h,静置24h,即可得到装载阿霉素的HM-alginate胶束溶液。
(3)载药胶束溶液和磁性微球的处理
a.配置一定浓度的N-羟基丁二酰亚胺(NHS,0.2mol/L)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC,0.8mol/L)溶液。
b.准确量取1mL的EDC溶液以1:1的比例与载药胶束混合以活化主链上的-COOH,置于摇床震荡1h,静置过夜。
c.准确量取NHS溶液与带有-NH2的磁性微球共2mL混合(NHS溶液与磁性微球用量比例如表1所示),置于摇床震荡1h,静置过夜。用激光扫描共聚焦显微镜选出形貌较好的比例进行下一步实验。
(4)在水溶液中,载药胶束与磁性微球结合,制备磁性靶向制剂
a.按步骤(3)中活化好的b,c分为2份,1份以2:1的比例直接混匀,另外一份每隔2h超声20min,共超声3次,再以2:1的比例混匀。反应24h。
b.将反应后的两份混合溶液磁性分离后,分别用去离子水洗涤三次,再定容至500μL。
c.在激发波长480nm,发射波长555nm处,用激光扫描共聚焦显微镜观察与磁性微球相连接的载药胶束的形貌,以确定载药胶束与带-NH2的磁性微球结合,使得水溶液中的载药胶束与疏水性药物成功分离,磁靶向制剂制备成功。
本发明所有试剂均为分析纯,实验用水为二次蒸馏水。
本发明所使用的NHS溶液(0.2mol/L)与EDC溶液(0.8mol/L)的配置方法是:准确称取NHS固体0.0462g溶于2mL去离子水,0.2303g固体EDC溶于1.5mL去离子水,分别摇匀。
本发明的干燥选用YB-真空恒温干燥箱(天津拓普仪器有限公司)
本发明的磁性分离选用磁力架(生工生物工程股份有限公司)
本发明的形貌观察选用激光扫描共聚焦显微镜(徕卡测量仪器有限公司)
本发明的显著效果
本发明是以阿霉素为疏水药物模型,系统研究了在水溶液中能自组装形成胶束的疏水改性海藻酸钠的载药性能。用带有-NH2的磁性微球与疏水改性海藻酸钠相连,不仅使在水溶液中的载药胶束与疏水性药物分离,而且制备了一种磁性靶向药物载体。通过研究HM-alginate与磁性微球的不同量比,是否超声等条件对实验进行优化。
当HM-alginate溶液的浓度为20mg/mL时,装载阿霉素后,探究HM-alginate与磁性微球的比例,发现当HM-alginate与磁性微球的比例为5:1时,在激光共聚焦下,磁靶向载药体系有较好的形貌。通过多次平行实验发现,结果相同,表明本发明具有良好的重现性。
本发明合成的磁靶向药物载体可用来装载不同的疏水性药物,从而形成稳定的磁靶向制剂。在一定的外加磁场的作用下,使得整个磁靶向体系在体内能够定向移动,在病变区聚集而后控制条件进行释放,从而达到对病变部位进行治疗的目的。磁靶向制剂与其他普通试剂或缓控试剂相比较而言,具有下列优点:1)靶向性,在一定的外加磁场作用下,载药微粒能够发生定向移动,最大程度的集中在病变部位。2)可适当的减少药物的使用剂量,从而减少毒副作用。3)对病变区具有特定作用,能够提高药物疗效。4)将药物释放后,载体骨架材料具有生物可降解性,对体内其他细胞没有影响。
附图说明
图1.载药胶束形貌,图a是未打开激光时,载药胶束的形貌;图b是打开激光,经激光激发后,装载阿霉素的胶束的形貌图。
图2.磁靶向制剂形貌,图a,b表示的是未超声时磁靶向制剂的形貌;图c,d表示的是超声后磁靶向制剂的形貌。
图3.载药胶束的磁性分离,图a是未分离时磁靶向制剂的形貌,图b是磁性分离后的磁靶向制剂的形貌。
具体实施方式
按照技术方案的步骤(1)-(3)得在水溶液中HM-alginate胶束、载药胶束、磁靶向制剂,其形貌见图1、图2,其中,海藻酸钠购自青岛明月海藻有限公司,十二烷基缩水甘油醚(DGE)、十二烷基硫酸钠(SDS)购自Maya Reagent,N-羟基丁二酰亚胺(NHS,0.2M)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)和阿霉素(Dox)购自aladdin。
按照技术方案的步骤(3)、(4)对得到的磁靶向制剂进行条件优化实验,通过激光共聚焦显微镜进行表征,具体见图3。
表1磁靶向药物载体实验条件比例优化
Claims (6)
1.一种磁靶向制剂的制备方法,其特征在于以带-NH2磁性微球为磁性物质,以改性后的海藻酸钠为药物载体骨架,以阿霉素为疏水性药物,通过化学反应实现磁靶向制剂的制备以及水溶液中载药胶束与疏水性药物的分离方法,合成步骤如下:
(1)疏水改性海藻酸钠的制备:准确称取5.0g海藻酸钠,加入70mL去离子水,机械搅拌后得到黄色均匀的乳状液。用氢氧化钠溶液(0.2mol/L)将溶液pH调节至9.0左右,缓慢滴加十二烷基缩水甘油醚(DGE)和十二烷基硫酸钠(SDS)各3mL,水浴加热至75℃后,回流反应8h。反应完成后冷却至室温,将混合液的pH用乙酸(1:1)调至4左右。用丙酮浸泡以除去混合物中的水、未反应的DGE和SDS,将析出后的产物进行过滤,再用丙酮浸泡12h。过滤后,将得到的淡黄色纤维状固体置于真空恒温干燥箱中干燥24h,干燥温度为60℃。
(2)载药胶束的制备:准确称取干燥后的疏水改性海藻酸钠0.2g,配置浓度为20mg/mL疏水改性海藻酸钠胶束溶液。搅拌均匀后加入2mg阿霉素,搅拌24h,静置24h,即可得到装载阿霉素的HM-alginate胶束溶液。
(3)载药胶束溶液和磁性微球的处理
a.配置一定浓度的N-羟基丁二酰亚胺(NHS,0.2mol/L)和1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC,0.8mol/L)溶液。
b.准确量取1mL的EDC溶液以1:1的比例与载药胶束混合以活化主链上的-COOH,置于摇床震荡1h,静置过夜。
c.准确量取NHS溶液与带有-NH2的磁性微球共2mL混合(NHS溶液与磁性微球的用量比例如表1所示),置于摇床震荡1h,静置过夜。用激光扫描共聚焦显微镜选出形貌较好的比例进行下一步实验。
(4)在水溶液中,载药胶束与磁性微球结合,制备磁性靶向制剂
a.按步骤(3)中活化好的b,c分为2份,1份以2:1的比例直接混匀,另外一份每隔2h超声20min,共超声3次,再以2:1的比例混匀。反应24h。
b.将反应后的两份混合溶液磁性分离后,分别用去离子水洗涤三次,再定容至500μL。
c.在激发波长480nm,发射波长555nm处,用激光扫描共聚焦显微镜观察与磁性微球相连接的载药胶束的形貌,以确定载药胶束与带-NH2的磁性微球结合,然后使用磁力架将水溶液中的载药胶束与疏水性药物成功分离,得到磁靶向制剂。
2.根据权利要求1的磁靶向制剂的制备方法,其特征在于所述化学试剂为分析纯试剂,所有溶液均用二次蒸馏水配置。
3.根据权利要求1的磁靶向制剂的制备方法,其特征在于所述NHS溶液(0.2mol/L)与EDC溶液(0.8mol/L)的配置方法是:准确称取NHS固体0.04615g溶于2mL去离子水,0.2303g固体EDC溶于1.5mL去离子水,分别摇匀。
4.根据权利要求1的磁靶向制剂的制备方法,其特征在于所述干燥选用YB-真空恒温干燥箱(天津拓普仪器有限公司)。
5.根据权利要求1的磁靶向制剂的制备方法,其特征在于所述磁性分离方法选用磁力架(生工生物工程股份有限公司)。
6.根据权利要求1的磁靶向制剂的制备方法,其特征在于所述形貌观察选用激光扫描共聚焦显微镜(徕卡测量仪器有限公司)。
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