CN110934831B - 二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料及其制备方法 - Google Patents
二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料及其制备方法 Download PDFInfo
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Abstract
本发明提供二甲基乙二酰甘氨酸‑白藜芦醇核壳型纳米材料及其制备方法，将二甲基乙二酰甘氨酸(DMOG)溶于1mL的二甲基亚砜(DMSO)中，得到二甲基乙二酰甘氨酸(DMOG)的二甲基亚砜(DMSO)溶液，将上述溶液分散于超纯水中，过滤后，得到二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液；将白藜芦醇溶解在PH为8.0‑9.0的磷酸盐缓冲液(PBS)中，将步骤1制备得到的二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液加入上述白藜芦醇溶液中，在室温20‑25℃下振荡反应10‑20h，过滤后，得到二甲基乙二酰甘氨酸‑白藜芦醇核壳型纳米材料。本发明制备方法简单，反应条件温和，制备的二甲基乙二酰甘氨酸‑白藜芦醇核壳型纳米材料粒径在105‑115nm，粒径分布均匀，核壳型结构明显。
Description
技术领域
本发明涉及生物医药技术领域，更具体地说涉及一种二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料及其制备方法。
背景技术
心肌梗死是由于冠状动脉供血不足，心肌急剧的暂时缺血与缺氧所引起的，最年来发病率显著增加，是全球最首要的致死原因之一。心肌梗死目前的治疗方法仅限于制备载体(例如水凝胶，支架)负载药物，这使得引入的载体会对人的机体产生一些不良影响，且治疗效果有待增强，因此，将药物自身制成纳米颗粒再通过静脉注射进入人体的方法应运而生。
纳米技术在当今时代发展迅速，由于一些药物非水溶性或稳定性较差，因此由纳米技术制备的纳米载体或药物纳米颗粒显得尤为重要。通过控制纳米颗粒的大小，表面电荷和结构可以实现药物的良好运输和可控释放，增强治疗效果。另外，这种纳米载药系统具有良好的生物相容性，能够极大的促进药物在病变部位的作用，使得治疗效率显著提高。
DMOG又名二甲基乙二酰甘氨酸，是α-酮戊二酸辅助因子的拮抗剂和HIFprolylhydroxylase的抑制剂，其还具有促进血管化的作用，因此广泛用于治疗心肌梗死。在小鼠局部缺血的骨骼肌中，DMOG抑制內源性HIF失活，诱导血管新生。在高血脂症大鼠体内，通过DMOG上调的缺氧诱导因子能够增强缺血后处理的心脏保护作用。
白藜芦醇是多酚类化合物，来源于花生、葡萄(红葡萄酒)、虎杖、桑椹等植物。其是肿瘤的化学预防剂，也是对降低血小板聚集，预防和治疗动脉粥样硬化、心脑血管疾病的化学预防剂。白藜芦醇可以通过减少心肌缺血-再灌注损伤、抑制动脉粥样硬化和血栓的形成、抗炎、抗氧化、舒张血管、等发挥心血管保护作用。生理浓度(0.1μmol/L)的白藜芦醇可以使血管舒张，因而能够起到降低血压和降低心血管病的风险的功能。
发明内容
本发明克服了现有技术中的不足，提供了一种二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料及其制备方法，本发明制备方法简单，反应条件温和，制备的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料粒径在105-115nm，粒径分布均匀，核壳型结构明显。
本发明的目的通过下述技术方案予以实现。
二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料及其制备方法，按照下述步骤进行：
步骤1，将二甲基乙二酰甘氨酸(DMOG)分散在二甲基亚砜(DMSO)中，得到二甲基乙二酰甘氨酸(DMOG)的二甲基亚砜(DMSO)分散液，将上述分散液分散于超纯水中，用纳米滤头过滤后，得到二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液；
步骤2，将白藜芦醇分散在PH为8.0-9.0的磷酸盐缓冲液(PBS)中，将步骤1制备得到的二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液加入上述白藜芦醇分散液中，在室温20-25℃下振荡反应10-20h，过滤、干燥后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料；
其中，二甲基乙二酰甘氨酸(DMOG)和白藜芦醇的质量比为1:(1-3)，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料为核壳结构，白藜芦醇壳体厚度为8-25nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为105-115nm。
二甲基乙二酰甘氨酸(DMOG)和白藜芦醇的质量比为1:(1-2)。
在步骤1中，对二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液过滤所使用的滤头粒径为210-230nm。
在步骤2中，磷酸盐缓冲液(PBS)的PH为8.2-8.5，反应时间为12-15h，对二甲基乙二酰甘氨酸(DMOG)纳米材料溶液过滤所使用的滤头粒径为210-230nm。
白藜芦醇壳体厚度为10-20nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为110-115nm。
本发明的有益效果为：本发明制备方法简单，反应条件温和，制备的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米粒子粒径在112nm左右，粒径分布均匀，核壳型结构明显。二甲基乙二酰甘氨酸(DMOG)和白藜芦醇形成的核壳结构纳米粒子，可以确保外层白藜芦醇在进入患病部位后先一步释放，待白藜芦醇药物释放完成后，内部DMOG药物粒子再进行释放，实现了前期抗炎后期促进血管化的效果。
附图说明
图1是本发明制备的二甲基乙二酰甘氨酸-白藜芦醇是核壳结构纳米材料的粒径分布图；
图2是本发明制备的二甲基乙二酰甘氨酸-白藜芦醇是核壳结构纳米材料的透射电镜图；
图3是本发明制备的二甲基乙二酰甘氨酸-白藜芦醇是核壳结构纳米材料的局部放大的透射电镜图。
具体实施方式
下面通过具体的实施例对本发明的技术方案作进一步的说明。
实施例1
pH＝8.5磷酸盐缓冲液(PBS缓冲液)的配制：
称取3.58g Na2HPO4·12H2O溶于50mL去离子H2O中得到0.2M Na2HPO4溶液；称取1.56g NaH2PO4·2H2O并溶于50mL去离子H2O中得到0.2M NaH2PO4溶液；然后用量筒量取40.5mL 0.2M Na2HPO4溶液和9.5mL 0.2M NaH2PO4溶液并将其混合、摇匀即可得到0.2M pH＝7.4PBS缓冲液。最后，在搅拌条件下用NaOH溶液对其进行pH调节，用精确pH试纸进行检测，最终得到0.2M pH＝8.5的磷酸缓冲液(PBS缓冲液)。
二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液的制备：
取10ml超纯水于小玻璃瓶，加小磁子高速搅拌，称取1mg二甲基乙二酰甘氨酸(DMOG)于1mL的二甲基亚砜(DMSO)中，配制1mg/mL的二甲基乙二酰甘氨酸(DMOG)的二甲基亚砜(DMSO)溶液，每次取10μL加入超纯水中，搅拌1min，重复取20次，共200μL。然后用220nm的滤头对其进行过滤即可制得二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液。
二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备：
将1.5mg白藜芦醇溶解在5mL，PH＝8.5的PBS缓冲液中，然后将5mL的DMOG NPs溶液加入其中，配制浓度为0.15mg/mL的白藜芦醇溶液，之后在室温20-25℃下利用摇床振荡反应12h；通过白藜芦醇的疏水作用，药物分子趋于其良溶剂二甲基亚砜(DMSO)，最终白藜芦醇包裹在二甲基乙二酰甘氨酸(DMOG)纳米粒子的表面，最终得到的溶液采用220nm的滤头对过滤后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料。
如图1所示，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料平均粒径为105-115nm,粒径分布数值为0.372，表明粒径分布较窄，说明制备的纳米粒子的粒径大小均一。
如图2，可以明显看出核壳结构，内部为二甲基乙二酰甘氨酸(DMOG)纳米粒子，外部为白藜芦醇壳体，白藜芦醇壳体的厚度约为8-25nm。
如图3，内部有多个二甲基乙二酰甘氨酸(DMOG)纳米粒子被白藜芦醇包裹，二甲基乙二酰甘氨酸(DMOG)纳米粒子在内部略有交叠，这可能是由于此为干态测试，粒子略有收缩。
实施例2
pH＝8.0磷酸盐缓冲液(PBS缓冲液)的配制：
称取3.58g Na2HPO4·12H2O溶于50mL去离子H2O中得到0.2M Na2HPO4溶液；称取1.56g NaH2PO4·2H2O并溶于50mL去离子H2O中得到0.2M NaH2PO4溶液；然后用量筒量取40.5mL 0.2M Na2HPO4溶液和9.5mL 0.2M NaH2PO4溶液并将其混合、摇匀即可得到0.2M pH＝7.4PBS缓冲液。最后，在搅拌条件下用NaOH溶液对其进行pH调节，用精确pH试纸进行检测，最终得到0.2M pH＝8.0的磷酸缓冲液(PBS缓冲液)。
二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液的制备：
取10ml超纯水于小玻璃瓶，加小磁子高速搅拌，称取1mg二甲基乙二酰甘氨酸(DMOG)于1mL的二甲基亚砜(DMSO)中，配制1mg/mL的二甲基乙二酰甘氨酸(DMOG)的二甲基亚砜(DMSO)溶液，每次取10μL加入超纯水中，搅拌1min，重复取20次，共200μL。然后用210nm的滤头对其进行过滤即可制得二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液。
二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备：
将1mg白藜芦醇溶解在5mL，PH＝8.0的PBS缓冲液中，然后将5mL的DMOG NPs溶液加入其中，配制浓度为0.1mg/mL的白藜芦醇溶液，之后在室温20-25℃下利用摇床振荡反应20h；通过白藜芦醇的疏水作用，药物分子趋于其良溶剂二甲基亚砜(DMSO)，最终白藜芦醇包裹在二甲基乙二酰甘氨酸(DMOG)纳米粒子的表面，最终得到的溶液采用210nm的滤头对过滤后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料。
实施例3
pH＝9.0磷酸盐缓冲液(PBS缓冲液)的配制：
称取3.58g Na2HPO4·12H2O溶于50mL去离子H2O中得到0.2M Na2HPO4溶液；称取1.56g NaH2PO4·2H2O并溶于50mL去离子H2O中得到0.2M NaH2PO4溶液；然后用量筒量取40.5mL 0.2M Na2HPO4溶液和9.5mL 0.2M NaH2PO4溶液并将其混合、摇匀即可得到0.2M pH＝7.4PBS缓冲液。最后，在搅拌条件下用NaOH溶液对其进行pH调节，用精确pH试纸进行检测，最终得到0.2M pH＝9.0的磷酸缓冲液(PBS缓冲液)。
二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液的制备：
取10ml超纯水于小玻璃瓶，加小磁子高速搅拌，称取1mg二甲基乙二酰甘氨酸(DMOG)于1mL的二甲基亚砜(DMSO)中，配制1mg/mL的二甲基乙二酰甘氨酸(DMOG)的二甲基亚砜(DMSO)溶液，每次取10μL加入超纯水中，搅拌1min，重复取20次，共200μL。然后用230nm的滤头对其进行过滤即可制得二甲基乙二酰甘氨酸(DMOG)纳米粒子溶液。
二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备：
将2mg白藜芦醇溶解在5mL，PH＝9.0的PBS缓冲液中，然后将5mL的DMOG NPs溶液加入其中，配制浓度为0.2mg/mL的白藜芦醇溶液，之后在室温20-25℃下利用摇床振荡反应15h；通过白藜芦醇的疏水作用，药物分子趋于其良溶剂二甲基亚砜(DMSO)，最终白藜芦醇包裹在二甲基乙二酰甘氨酸(DMOG)纳米粒子的表面，最终得到的溶液采用230nm的滤头对过滤后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料。
以上对本发明做了示例性的描述，应该说明的是，在不脱离本发明的核心的情况下，任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (10)
1.二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其特征在于：二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料为核壳结构，白藜芦醇为壳体，二甲基乙二酰甘氨酸为内核，白藜芦醇壳体厚度为8-25nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为105-115nm，按照下述步骤进行：
步骤1，将二甲基乙二酰甘氨酸分散在二甲基亚砜中，得到二甲基乙二酰甘氨酸的二甲基亚砜分散液，将上述分散液分散于超纯水中，用纳米滤头过滤后，得到二甲基乙二酰甘氨酸纳米粒子溶液；
步骤2，将白藜芦醇分散在PH为8.0-9.0的磷酸盐缓冲液中，将步骤1制备得到的二甲基乙二酰甘氨酸纳米粒子溶液加入上述白藜芦醇分散液中，在室温20-25℃下振荡反应10-20h，过滤、干燥后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其中，二甲基乙二酰甘氨酸和白藜芦醇的质量比为1:(1-3)。
2.根据权利要求1所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其特征在于：二甲基乙二酰甘氨酸和白藜芦醇的质量比为1:(1-2)。
3.根据权利要求1所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其特征在于：在步骤1中，对二甲基乙二酰甘氨酸纳米材料溶液过滤所使用的滤头粒径为210-230nm。
4.根据权利要求1所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其特征在于：在步骤2中，磷酸盐缓冲液的PH为8.2-8.5，反应时间为12-15h，在步骤1中，对二甲基乙二酰甘氨酸纳米粒子溶液过滤所使用的滤头粒径为210-230nm。
5.根据权利要求1所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料，其特征在于：白藜芦醇壳体厚度为10-20nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为110-115nm。
6.制备如权利要求1-5任一所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的方法，其特征在于：按照下述步骤进行：
步骤1，将二甲基乙二酰甘氨酸分散在二甲基亚砜中，得到二甲基乙二酰甘氨酸的二甲基亚砜分散液，将上述分散液分散于超纯水中，用纳米滤头过滤后，得到二甲基乙二酰甘氨酸纳米粒子溶液；
步骤2，将白藜芦醇分散在PH为8.0-9.0的磷酸盐缓冲液中，将步骤1制备得到的二甲基乙二酰甘氨酸纳米粒子溶液加入上述白藜芦醇分散液中，在室温20-25℃下振荡反应10-20h，过滤、干燥后，得到二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料；
其中，二甲基乙二酰甘氨酸和白藜芦醇的质量比为1:(1-3)，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料为核壳结构，白藜芦醇壳体厚度为8-25nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为105-115nm。
7.根据权利要求6所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备方法，其特征在于：二甲基乙二酰甘氨酸和白藜芦醇的质量比为1:(1-2)。
8.根据权利要求6所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备方法，其特征在于：在步骤1中，对二甲基乙二酰甘氨酸纳米材料溶液过滤所使用的滤头粒径为210-230nm。
9.根据权利要求6所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备方法，其特征在于：在步骤2中，磷酸盐缓冲液的PH为8.2-8.5，反应时间为12-15h，在步骤1中，对二甲基乙二酰甘氨酸纳米粒子溶液过滤所使用的滤头粒径为210-230nm。
10.根据权利要求6所述的二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的制备方法，其特征在于：白藜芦醇壳体厚度为10-20nm，二甲基乙二酰甘氨酸-白藜芦醇核壳型纳米材料的粒径为110-115nm。
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