CN103239455A - 有协同治疗效果和高载药量的多组分纳米药物的制备方法 - Google Patents
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Abstract
本发明公开了有协同治疗效果和高载药量的多组分纳米药物的制备方法，包括以下步骤：步骤1）将甲氨蝶呤，10-羟基喜树碱和紫杉醇三种疏水抗癌药物质量比为1：1：1溶解于二甲亚砜中，超声5分钟，使之形成浓度为3mg/mL混合溶液；步骤2）取体积为400μL的所述混合溶液滴加到超纯水中，磁力搅拌，获得多组分纳米药物的悬浮液；步骤3）在所述多组分纳米药物悬浮液中加入浓度为1mg/mL，体积为300μL的聚马来酸酐18碳烯-聚乙二醇，超声分散5分钟，静置3小时。本发明简单有效，重复性强，可控性好，普适性强，为癌症领域中应用于多药协同治疗的纳米药物的制备提供了实验依据。
Description
技术领域
本发明涉及生物制药领域，具体涉及的是有协同治疗效果和高载药量的多组分纳米药物的制备方法。
背景技术
近年来，化疗作为一种有效的肿瘤治疗方法在临床上有着重要的应用，而多药组合化疗由于其组合药效的增强以及对细胞耐药性的抑制作用在医学领域中显示出极大的应用潜力。2010年，Y. Q. Shen小组通过用一种疏水性化疗药物喜树碱代替磷酸脂质体中的脂肪酸，形成一种类磷酸脂质体的载体结构，同时装载另一种化疗药物盐酸阿霉素。所得的多药纳米胶囊表现出优于两种单体药物的疗效，体现了协同治疗效果（Shen, Y. Q.; Jin, E. L.; Zhang. B.; Murphy, C. J.; Sui, M. H.; Zhao, J.; Wang, J. Q.; Tang, J. B.; Fan, M.H.; Kirk, E. V.; Murdoch, V. J. J. Am. Chem. Soc. 2010, 132 , 4259–4265）。2012年，J. L. Shi小组制备了一种中空的无机多孔硅纳米胶囊，同时装载喜树碱和盐酸阿霉素两种化疗药物，针对耐药细胞有良好的治疗效果（Chen, Y. G.; Chen, H. R.; Zeng, D. P.; Li, Y. P.; Zheng, Y. Y.; Li, F. Q.; Ji, X. F.; Wang, X.; Chen, F.; He, Q. J.; Zhang, L. L.; Shi, J. L. Adv. Funct. Mater. 2012, 22, 1586-1597）。
如果能实现药物的组合治疗，无疑为化疗药物在癌症治疗领域的发展带来新的机遇。通常的解决思路是通过制备一种纳米尺寸的载体，直接载入两种不同的化疗药物，通过载体传输到治疗部位。该方法在一定程度上提高了药物的化疗效果，然而也存在一定的局限性，如载药量较低，纳米载体制备工艺复杂以及载体潜在的毒副作用与体内降解等问题。(Barreto, J. A.; O'Malley, W.; Kubeil, M.; Graham, B.; Stephan, H.; Spiccia, L. Adv. Mater. 2011, 23, H18-H40）。因此，提高纳米多药组合治疗的载药量以及尽可能少的使用外来载体的用量，无疑对实现癌症治疗的实际应用有重要的意义。
发明内容
本发明的目的在于克服现有技术存在的以上问题，提供有协同治疗效果和高载药量的多组分纳米药物的制备方法，通过简单的溶剂交换法，首次实现了无载体的多药纳米药物的制备，通过多药纳米结构自身做载体实现药物传输。
为实现上述技术目的，达到上述技术效果，本发明通过以下技术方案实现：
有协同治疗效果和高载药量的多组分纳米药物的制备方法，包括以下步骤：
步骤1）将甲氨蝶呤，10-羟基喜树碱和紫杉醇三种疏水抗癌药物质量比为1：1：1溶解于二甲亚砜中，超声5分钟，使之形成浓度为3 mg/mL混合溶液；
步骤2）取体积为400 μL的所述混合溶液滴加到超纯水中，磁力搅拌，获得多组分纳米药物的悬浮液；
步骤3）在所述多组分纳米药物悬浮液中加入浓度为1 mg/mL，体积为300 μL的聚马来酸酐18碳烯-聚乙二醇，超声分散5分钟，静置3小时。
进一步的，所述步骤1中的二甲亚砜和所述步骤2中的超纯水体积比为1:25。
进一步的，所述步骤2的反应温度为0 ℃，反应条件为磁力搅拌3分钟，转速为1000 rad。
本发明的有益效果是:
1、多种药物组合治疗，可以增强药效，抑制肿瘤细胞对单一药物的耐药性；
2、多组分纳米药物无需任何惰性载体的载入，载药量大大提高，并且有效避免了载体的生物毒性和体内代谢问题；
3、在多组分纳米药物表面的修饰简单易行，表面修饰后的多组分纳米药物生物环境稳定；
4、实验操作方法简单，重复性高，可控性强。；
5、制备方法具有普适性，对于一系列的疏水性抗癌药物的组合均适用；
附图说明
图1为多组分纳米药物的扫描电子显微镜图片；
图2为多组分纳米药物和经C18PMH-PEG表面亲水性修饰的纳米药物在C18PMH-PEG修饰前后的动力学尺寸分布图片；
图3经过亲水性表面修饰前后的MDNCs和MDNCs-PEG在生理盐水中的尺寸变化曲线；
图 4 为多组分纳米药物及其单一药物组分对宫颈癌细胞的毒性测试图；
图 5 为多组分纳米药物及其单一药物组分对乳腺癌细胞的毒性测试图。
具体实施方式
下面将参考附图并结合实施例，来详细说明本发明。
参照图1所示，有协同治疗效果和高载药量的多组分纳米药物的制备方法，包括以下步骤：
步骤1）将甲氨蝶呤，10-羟基喜树碱和紫杉醇三种疏水抗癌药物质量比为1：1：1溶解于二甲亚砜中，超声5分钟，使之形成浓度为3 mg/mL混合溶液；
步骤2）取体积为400 μL的所述混合溶液滴加到超纯水中，磁力搅拌，获得多组分纳米药物的悬浮液；
步骤3）在所述多组分纳米药物悬浮液中加入浓度为1 mg/mL，体积为300 μL的聚马来酸酐18碳烯-聚乙二醇，超声分散5分钟，静置3小时。
进一步的，所述步骤1中的二甲亚砜和所述步骤2中的超纯水体积比为1:25。
进一步的，所述步骤2的反应温度为0 ℃，反应条件为磁力搅拌3分钟，转速为1000 rad。
Claims (3)
1.有协同治疗效果和高载药量的多组分纳米药物的制备方法，其特征在于，包括以下步骤：
步骤1）将甲氨蝶呤，10-羟基喜树碱和紫杉醇三种疏水抗癌药物质量比为1：1：1溶解于二甲亚砜中，超声5分钟，使之形成浓度为3 mg/mL混合溶液；
步骤2）取体积为400 μL的所述混合溶液滴加到超纯水中，磁力搅拌，获得多组分纳米药物的悬浮液；
步骤3）在所述多组分纳米药物悬浮液中加入浓度为1 mg/mL，体积为300 μL的聚马来酸酐18碳烯-聚乙二醇，超声分散5分钟，静置3小时。
2.根据权利要求1所述的有协同治疗效果和高载药量的多组分纳米药物的制备方法，其特征在于：所述步骤1中的二甲亚砜和所述步骤2中的超纯水体积比为1:25。
3.根据权利要求1所述的有协同治疗效果和高载药量的多组分纳米药物的制备方法，其特征在于，所述步骤2的反应温度为0 ℃，反应条件为磁力搅拌3分钟，转速为1000 rad。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550776A (zh) * | 2013-10-31 | 2014-02-05 | 国家纳米科学中心 | 一种疏水性药物纳米颗粒、其制备方法和应用 |
| CN103622920A (zh) * | 2013-11-29 | 2014-03-12 | 国家纳米科学中心 | 一种包含抗癌药物的纳米颗粒、其制备方法和应用 |
| CN112512587A (zh) * | 2018-08-06 | 2021-03-16 | 第一三共株式会社 | 抗体药物缀合物和微管蛋白抑制剂的组合 |
-
2012
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Non-Patent Citations (3)
| Title |
|---|
| WEI LI，ET AL: "Carrier-free，functionalized drug nanoparticles for targeted drug delivery", 《CHEM.COMMUN.》 * |
| XIAOJUN DIAO,ET AL: "Carrier-free,water dispersible and highly luminescent dye nanoparticles for targeted cell imaging", 《NANOSCALE》 * |
| 张成义，等: "溶剂交换法制备一维有机纳米材料", 《影像科学与光化学》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550776A (zh) * | 2013-10-31 | 2014-02-05 | 国家纳米科学中心 | 一种疏水性药物纳米颗粒、其制备方法和应用 |
| CN103550776B (zh) * | 2013-10-31 | 2016-06-08 | 国家纳米科学中心 | 一种疏水性药物纳米颗粒、其制备方法和应用 |
| CN103622920A (zh) * | 2013-11-29 | 2014-03-12 | 国家纳米科学中心 | 一种包含抗癌药物的纳米颗粒、其制备方法和应用 |
| CN112512587A (zh) * | 2018-08-06 | 2021-03-16 | 第一三共株式会社 | 抗体药物缀合物和微管蛋白抑制剂的组合 |
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Application publication date: 20130814 |