CN114588272B - 一种负载no的多西紫杉醇纳米药物及其制备方法和应用 - Google Patents
一种负载no的多西紫杉醇纳米药物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种负载一氧化氮(NO)的多西紫杉醇纳米药物及其制备方法和应用，所述纳米药物是由NO供体多西紫杉醇偶联物自组装而成，所述NO供体多西紫杉醇偶联物为NO供体通过化学键与多西紫杉醇连接所形成的偶联物。本发明公开的负载NO的多西紫杉醇纳米药物稳定性好，能控制释放NO，增强多西紫杉醇的细胞毒性。
Description
技术领域
本发明涉及药物制剂领域，具体涉及一种负载NO的多西紫杉醇纳米药物及其制备方法和应用。
背景技术
癌症是危害人类健康的主要疾病之一，且难以治愈。目前，癌症的主要治疗方法包括手术、化疗、免疫治疗和放疗，其中，化疗是主要的治疗方法，也是必不可少的辅助治疗方法。多西紫杉醇是当前最具代表性的抗癌化疗药物。然而，多西紫杉醇是水溶性差，临床使用时需要助溶剂配合，降低了治疗效果，同时还会引起副作用。此外，多西紫杉醇还缺乏靶向性，用药时除了杀死肿瘤细胞外还会杀死正常细胞，更重要的是，长期使用会导致多药耐药性。
目前，两亲性小分子前药自组装构建纳米给药系统是一种非常有吸引力的方法，其为无载体递药系统，可以大幅度增加药物载药量，提高药物的溶解度，增强药物的靶向性。因此，用多西紫杉醇作为疏水片段设计两亲性小分子前药并自组装成纳米给药系统能有效解决多西紫杉醇的缺点。
一氧化氮(NO)作为体内重要的效应分子，参与多种病理生理过程，且具有抗肿瘤、抗菌、抗血小板、抗炎等多种药理作用。在肿瘤研究领域，NO更是展现出多面性。高浓度的NO可通过损伤DNA或抑制DNA修复直接杀死肿瘤细胞。低浓度NO可促进肿瘤血管生成，抑制P糖蛋白，提高肿瘤对化疗药物的敏感性。因此，构建无载体负载NO的多西紫杉醇纳米药物具有重要意义。
发明内容
发明目的：本发明基于目前存在的客观难题，提供一种负载NO的多西紫杉醇纳米药物及其制备方法和应用，以此解决了多西紫杉醇水溶性差、靶向性不足，易产生耐药性等不足，提高肿瘤治疗效果。
技术方案：为了达到上述发明目的，本发明所采用的技术方案如下：
一种负载NO的多西紫杉醇纳米药物，所述纳米药物是由NO供体多西紫杉醇偶联物自组装而成，所述NO供体多西紫杉醇偶联物为NO供体通过化学键与多西紫杉醇连接所形成的偶联物。
优选的，所述NO供体多西紫杉醇偶联物的分子结构式如下：
优选的，所述NO供体选自但不局限于硝酸酯类、硝普盐类、S-亚硝基硫醇类、呋咱氮氧化物类或偶氮鎓二醇盐类。
优选的，所述化学键选自但不局限于酰胺键、酯键或缩醛键。
优选的，所述NO供体多西紫杉醇偶联物中，一个多西紫杉醇分子上连接NO供体的数量为1-4个。
所述负载NO的多西紫杉醇纳米药物的制备方法，包括以下步骤：将所述NO供体多西紫杉醇偶联物溶于乙醇中，然后与稳定剂混合，再在超声条件下将去离子水缓慢滴加到混合溶液中，透析除去有机溶剂，最后得到所述纳米药物的溶液。
优选的，所述稳定剂选自维生素E聚乙二醇琥珀酸酯乙醇，其与NO供体多西紫杉醇偶联的质量比为1:(180-220)。
优选的，所述NO供体多西紫杉醇偶联物的制备方法包括以下步骤：
(1)取单硝酸异山梨酯和丁二酸酐，混合溶解，再缓慢加入4-二甲氨基吡啶(DMAP)，室温搅拌反应，得到中间体。
(2)室温下，取多西紫杉醇和中间体混合，加入干燥N,N-二甲基甲酰胺，冰浴下缓慢加入1-乙基-3-(3-二甲基丙胺)碳二亚胺EDCI和DMAP，室温搅拌反应，萃取，干燥，分离，即得所述NO供体多西紫杉醇偶联物。
进一步优选的，步骤(1)中，所述单硝酸异山梨酯和丁二酸酐的摩尔比为1：1；步骤(2)中，所述多西紫杉醇和中间体的摩尔比为1:(1-2)。
本发明最后提供了所述负载NO的多西紫杉醇纳米药物在制备抗肿瘤药物中的应用。
优选的，所述肿瘤包括但不局限于卵巢癌、乳腺癌、肺癌、大肠癌、脑胶质瘤、宫颈癌或黑色素瘤。
有益效果：与现有技术相比，本发明具有以下优势：
1、本发明提供的负载NO的多西紫杉醇纳米药物制备简单，稳定性好，易放大制备。
2、本发明提供的负载NO的多西紫杉醇纳米药物为无载体纳米递药体系，载药量高，具有被动靶向能力，体循环时间长，药物药动学性质得到改善。
3、本发明提供的负载NO的多西紫杉醇纳米药物实现了NO治疗和化疗联合；能可控释放NO，改善肿瘤细胞对化疗药物的敏感性。
附图说明
图1：实施例2中负载NO的多西紫杉醇纳米药物的粒径图和透射电子显微镜图；
图2：实施例3中负载NO的多西紫杉醇纳米药物的稳定性；
图3：实施例4中负载NO的多西紫杉醇纳米药物控制释放NO的性能；
具体实施方式
下面通过实施例对本发明加以进一步的说明，但下述实施例并不限制本专利的权利范围。
实施例1：单硝酸异山梨酯多西紫杉醇偶联物(ISMN-DTX)的合成，过程如下：
室温下，将单硝酸异山梨酯和丁二酸酐置于茄形瓶中，用二氯甲烷溶解，再缓慢加入4-二甲氨基吡啶(DMAP)，室温搅拌反应。TLC监测反应完成后，向反应液中加入20mL水，混合液用乙酸乙酯(20mL×3)萃取，合并有机层，用饱和氯化钠溶液洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱色谱分离后纯化然后得到中间体。
室温下，将多西紫杉醇和中间体置于茄形瓶中，加入10mL干燥N,N-二甲基甲酰胺，冰浴下缓慢加入1-乙基-3-(3-二甲基丙胺)碳二亚胺EDCI和DMAP，室温搅拌反应，TLC监测反应完成，向反应液中加入20mL水，混合液用乙酸乙酯(20mL×3)萃取，合并有机层，用饱和氯化钠溶液洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱色谱分离纯化得到ISMN-DTX。
实施例2：负载NO的多西紫杉醇纳米药物的制备及粒径的测定
负载NO的多西紫杉醇纳米药物采用溶剂交换法制备。首先制备4mg/mL的ISMN-DTX的乙醇溶液。然后将100μL的ISMN-DTX溶液与40μL的5％维生素E聚乙二醇琥珀酸酯(TPGS)乙醇溶液混合。超声条件下滴加去离子水，最终浓度控制为0.4mg/mL。此后，用去离子水透析(Spectra/Pore，MWCO 1000)。负载NO的多西紫杉醇纳米药物的粒径和外貌用动态光散射和透射电子显微镜观察，结果显示制备的纳米药物能成单分散的纳米粒子，水合粒径为164.5nm，粒径分布指数为0.195，电镜结果显示纳米药物为球形的，如图1所示。
实施例3：负载NO的多西紫杉醇纳米药物稳定性评价
为了研究负载NO的多西紫杉醇纳米药物的储存稳定性，利用DLS监测负载NO的多西紫杉醇纳米药物分别在第0天、第3天、第6天和第9天测量制备的纳米药物的尺寸分布。结果显示，负载NO的多西紫杉醇纳米药物在检测期间粒径和粒径分布指数均没有明显变化，说明其具有很好的稳定性，如图2所示。
实施例4：负载NO的多西紫杉醇纳米药物控释NO评价
采用Griess试剂测定负载NO的多西紫杉醇纳米药物体外释放NO的量。将负载NO的多西紫杉醇纳米药物(约10μM NO)置于37℃下用10mM GSH刺激。在指定的时间点，收集介质，并补加等体积的介质。收集的介质与Griess试剂在室温下混合10min，然后用酶标仪测定，检测NO的释放量。未用GSH刺激的负载NO的多西紫杉醇纳米药物作为对照。结果显示，在GSH刺激下NO能从纳米药物中缓慢释放出来，而在相同条件下，未用GSH刺激释放NO的量检测不到，说明负载NO的多西紫杉醇纳米药物能实现NO的控制释放，如图3所示。
以上所述，仅是本发明的一般性说明，并非对本发明做任何形式上的限制。任何其他相关人员依据本发明相关内容做任何变动，均属本发明保护范畴。
Claims (6)
1.一种负载NO的多西紫杉醇纳米药物，其特征在于，所述纳米药物是由NO供体多西紫杉醇偶联物自组装而成，所述NO供体多西紫杉醇偶联物为NO供体通过化学键与多西紫杉醇连接所形成的偶联物，所述NO供体多西紫杉醇偶联物的分子结构式如下：
2.权利要求1所述的负载NO的多西紫杉醇纳米药物的制备方法，其特征在于，包括以下步骤：将所述NO供体多西紫杉醇偶联物溶于乙醇中，然后与稳定剂混合，再在超声条件下将去离子水缓慢滴加到混合溶液中，透析除去有机溶剂，最后得到所述纳米药物的溶液。
3.根据权利要求2所述的负载NO的多西紫杉醇纳米药物的制备方法，其特征在于，所述稳定剂选自维生素E聚乙二醇琥珀酸酯乙醇。
4.根据权利要求2所述的负载NO的多西紫杉醇纳米药物的制备方法，其特征在于，所述NO供体多西紫杉醇偶联物的制备方法包括以下步骤：
(1)取单硝酸异山梨酯和丁二酸酐，混合溶解，再缓慢加入4-二甲氨基吡啶(DMAP)，室温搅拌反应，得到中间体。
(2)室温下，取多西紫杉醇和中间体混合，加入干燥DMF，冰浴下缓慢加入EDCI和DMAP，室温搅拌反应，萃取，干燥，分离，即得所述NO供体多西紫杉醇偶联物。
5.权利要求1所述的负载NO的多西紫杉醇纳米药物在制备抗肿瘤药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述肿瘤包括卵巢癌、乳腺癌、肺癌、大肠癌、脑胶质瘤、宫颈癌或黑色素瘤。
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