CN117085146B - 一种金属框架制备方法及其靶向激活内质网应激的用途 - Google Patents
一种金属框架制备方法及其靶向激活内质网应激的用途 Download PDFInfo
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Abstract
本发明公开了一种金属框架制备方法及其靶向激活内质网应激的用途，涉及生物医药技术领域，其方法步骤包括如下：步骤S1：通过一锅法制备装载有千金藤素的铁基金属框架材料，步骤S2：通过派派堆积效应，将靶向配体格列本脲修饰到装载有千金藤素的铁基金属框架材料表面，步骤S3：用特定浓度的该纳米药物处理肿瘤细胞；通过装载千金藤素的金属框架材料，并在其表面修饰上靶向配体格列本脲，修饰上靶向配体的纳米药物能够在靶细胞及其细胞器里大量富集，在精准治疗的同时降低了药物对正常器官的毒副作用，从而解决了药物往往存在靶向性差等问题，在肿瘤细胞内质网的蓄积量极低，限制了其临床疗效的问题。
Description
技术领域
本发明涉及生物医药技术领域，具体为一种金属框架制备方法及其靶向激活内质网应激的用途。
背景技术
在肿瘤的发生、发展及转移过程中，肿瘤细胞经历的缺氧、低糖、酸中毒等应激环境，使肿瘤细胞发生内质网应激，内质网应激启动未折叠蛋白反应使细胞恢复稳态；但当内质网应激超过细胞的存活能力时，则会介导细胞凋亡。临床上，在一些蒽醌类及奥沙利铂等药物的作用下，产生过度的内质网应激，从而介导肿瘤细胞的免疫原性细胞死亡并激发抗肿瘤免疫反应，在治疗后期形成长期免疫记忆。但是，这些药物往往存在靶向性差等问题，在肿瘤细胞内质网的蓄积量极低，限制了其临床疗效。因此，内质网靶向药物的研究将会提供更高效更精准的抗肿瘤免疫治疗策略；
目前，临床上在一些蒽醌类及奥沙利铂等药物的作用下，产生过度的内质网应激，从而介导肿瘤细胞的免疫原性细胞死亡并激发抗肿瘤免疫反应，在治疗后期形成长期免疫记忆。但是，这些药物往往存在靶向性差等问题，在肿瘤细胞内质网的蓄积量极低，限制了其临床疗效；本发明的目的在于通过安全有效且经济稳定的方法制备一种靶向激活内质网应激的纳米药物。
发明内容
针对现有技术的不足，本发明提供了一种金属框架制备方法及其靶向激活内质网应激的用途，解决了背景技术中所提出药物往往存在靶向性差等问题，在肿瘤细胞内质网的蓄积量极低，限制了其临床疗效的问题。
为实现以上目的，本发明通过以下技术方案予以实现：一种金属框架制备方法及其靶向激活内质网应激的用途，其方法步骤包括如下：
步骤S1：通过一锅法制备装载有千金藤素的铁基金属框架材料，将FeCl3/6H2O溶液(2mL,15mg/mL-1，溶于DMF)、TCPP溶液(4mL,2.5mg/mL-1,溶于DMF)和苯甲酸(4mL,70mg/mL-1,溶于DMF)相互混匀后，Cep溶液(4mL,6mg/mL-1,溶于DMF)缓慢滴加到其中，得到反应液A；反应液A处理后在室温下真空干燥，得到固体粉末产品Cep@MOF；
步骤S2：通过派派堆积效应，将靶向配体格列本脲修饰到装载有千金藤素的铁基金属框架材料表面，通过将Cep@MOF溶液(20mL,1mg/mL-1,溶于DMF)和格列本脲(Gli,2mL,5mg/mL-1,溶于DMF)搅拌反应；反应完后，离心，用DMF清洗并真空干燥，得到固体粉末产品Cep@Gli-MOF；
步骤S3：用特定浓度的该纳米药物处理肿瘤细胞；
步骤S4：通过激光共聚焦实验和CCK8实验，评估该纳米药物靶向富集在内质网的情况，以及抗肿瘤效应。
优选的，装载的药物包括但不局限于千金藤素，可为一个或多个相同或不同的化疗药物：奥沙利铂、蒽醌类。
优选的，所述铁基金属框架材料，是以铁离子为金属结点的金属框架材料MOFs。
优选的，靶向内质网的配体包括不局限于格列本脲，可为对甲苯磺酰胺、萘磺酰胺、维生素B6、KDEL肽、Eriss肽、RARC肽、KKXX肽、Pardaxin肽。
优选的，所述步骤S2中制得的Cep@Gli-MOF通过扫描电镜(SEM)、透射电镜(TEM)、紫外-可见吸收光谱分析、红外光谱分析和动态光散射技术来表征粒径的分布，从而得知制得的Cep@Gli-MOF为分布均匀的球形纳米颗粒，粒径为55nm。
优选的，所述步骤S3中处理肿瘤细胞的步骤包括如下：
A.在激光共聚焦培养皿(35mm)接种8×104个HepG2细胞；
B.培养24h后，用pH 7.4的PBS溶液小心洗涤三遍；
C.在含有20μg/mL-1的Cep@Gli-MOF培养基里孵育3h后，移除培养基，用pH 7.4的PBS溶液小心洗涤三遍；
D.用50nM的ER-Tracker在37℃下孵育60min后，用pH 7.4的PBS溶液小心洗涤三遍；加入4％多聚甲醛在室温下固定15min随后用4’,6-二脒基-2-苯基吲哚(DAPI)染色细胞核15min；
E.最后用PBS润洗后，置于激光共聚焦下观察可以看到，装载千金藤素的金属框架Cep@Gli-MOF能靶向富集至肿瘤细胞内质网；
优选的，所述步骤S1中反应液A处理方法为将反应液A在90℃下回流加热5h，待反应完后，离心，用DMF洗三次。
优选的，所述步骤S2中用DMF清洗次数为三次，在温度23℃±2℃下真空干燥。
优选的，所述步骤S2中Cep@MOF溶液和格列本脲在温度23℃±2℃下搅拌，搅拌时间为4h。
本发明提供了一种金属框架制备方法及其靶向激活内质网应激的用途。具备以下有益效果：
通过装载千金藤素的金属框架材料，并在其表面修饰上靶向配体格列本脲。纳米尺度的该纳米药物具备渗透与滞留(Enhanced penetration and retention,EPR)靶向效应，能穿透新生血管富集致癌组织，同时，该纳米药物表面修饰的靶向配体格列本脲可以高度结合定位在内质网上ATP敏感的钾离子通道磺脲类受体，从而能主动靶向至内质网，进一步的，千金藤素和金属框架材料能够协同诱导内质网应激，介导肿瘤细胞凋亡，通过修饰上靶向配体的纳米药物能够在靶细胞及其细胞器里大量富集，在精准治疗的同时降低了药物对正常器官的毒副作用，从而解决了药物往往存在靶向性差等问题，在肿瘤细胞内质网的蓄积量极低，限制了其临床疗效的问题。
附图说明
图1为本发明步骤示意图；
图2为本发明装载千金藤素的金属框架透射电镜图；(A图标尺100nm；B图标尺20nm)；
图3为本发明激光共聚焦检测示意图；(标尺：50μm)；
图4为本发明技术方案流程示意图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整的描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：
一种金属框架制备方法及其靶向激活内质网应激的用途，其方法步骤包括如下：
步骤S1：通过一锅法制备装载有千金藤素的铁基金属框架材料，将FeCl3/6H2O溶液(2mL,15mg/mL-1，溶于DMF)、TCPP溶液(4mL,2.5mg/mL-1,溶于DMF)和苯甲酸(4mL,70mg/mL-1,溶于DMF)相互混匀后，Cep溶液(4mL,6mg/mL-1,溶于DMF)缓慢滴加到其中，得到反应液A；反应液A处理后在室温下真空干燥，得到固体粉末产品Cep@MOF；
步骤S2：通过派派堆积效应，将靶向配体格列本脲修饰到装载有千金藤素的铁基金属框架材料表面，通过将Cep@MOF溶液(20mL,1mg/mL-1,溶于DMF)和格列本脲(Gli,2mL,5mg/mL-1,溶于DMF)搅拌反应；反应完后，离心，用DMF清洗并真空干燥，得到固体粉末产品Cep@Gli-MOF；
步骤S3：用特定浓度的该纳米药物处理肿瘤细胞；
步骤S4：通过激光共聚焦实验和CCK8实验，评估该纳米药物靶向富集在内质网的情况，以及抗肿瘤效应。
装载的药物包括但不局限于千金藤素，可为一个或多个相同或不同的化疗药物：奥沙利铂、蒽醌类。
所述铁基金属框架材料，是以铁离子为金属结点的金属框架材料MOFs。
靶向内质网的配体包括不局限于格列本脲，可为对甲苯磺酰胺、萘磺酰胺、维生素B6、KDEL肽、Eriss肽、RARC肽、KKXX肽、Pardaxin肽。
所述步骤S2中制得的Cep@Gli-MOF通过扫描电镜(SEM)、透射电镜(TEM)、紫外-可见吸收光谱分析、红外光谱分析和动态光散射技术来表征粒径的分布，从而得知制得的Cep@Gli-MOF为分布均匀的球形纳米颗粒，粒径为55nm。
所述步骤S3中处理肿瘤细胞的步骤包括如下：
A.在激光共聚焦培养皿(35mm)接种8×104个HepG2细胞；
B.培养24h后，用pH 7.4的PBS溶液小心洗涤三遍；
C.在含有20μg/mL-1的Cep@Gli-MOF培养基里孵育3h后，移除培养基，用pH 7.4的PBS溶液小心洗涤三遍；
D.用50nM的ER-Tracker在37℃下孵育60min后，用pH 7.4的PBS溶液小心洗涤三遍；加入4％多聚甲醛在室温下固定15min随后用4’,6-二脒基-2-苯基吲哚(DAPI)染色细胞核15min；
E.最后用PBS润洗后，置于激光共聚焦下观察可以看到，装载千金藤素的金属框架Cep@Gli-MOF能靶向富集至肿瘤细胞内质网；
所述步骤S1中反应液A处理方法为将反应液A在90℃下回流加热5h，待反应完后，离心，用DMF洗三次。
所述步骤S2中用DMF清洗次数为三次，在温度23℃±2℃下真空干燥。
所述步骤S2中Cep@MOF溶液和格列本脲在温度23℃±2℃下搅拌，搅拌时间为4h。
实施例2：
参见图4和图2所示，一种装载千金藤素的金属框架制备方法，包括以下步骤：
A.将FeCl3/6H2O溶液(2mL,15mg/mL-1，溶于DMF)、TCPP溶液(4mL,2.5mg/mL-1,溶于DMF)和苯甲酸(4mL,70mg/mL-1,溶于DMF)相互混匀后，Cep溶液(4mL,6mg/mL-1,溶于DMF)缓慢滴加到其中。上述反应液在90℃下回流加热5h。待反应完后，离心，用DMF洗三次，在室温下真空干燥，得到固体粉末产品Cep@MOF。
B.将Cep@MOF溶液(20mL,1mg/mL-1,溶于DMF)和格列本脲(Gli,2mL,5mg/mL-1,溶于DMF)在室温下搅拌4h。反应完后，离心，用DMF洗三次，在室温下真空干燥，得到固体粉末产品Cep@Gli-MOF。
C.将实例2中制得的Cep@Gli-MOF通过扫描电镜(SEM)、透射电镜(TEM)、紫外-可见吸收光谱分析、红外光谱分析和动态光散射技术来表征粒径的分布。
D.由图2可以看到，制得的Cep@Gli-MOF为分布均匀的球形纳米颗粒，粒径为55nm。
实施例3：
参见图3所示，装载千金藤素的金属框架靶向富集至肿瘤细胞内质网，包括以下步骤：
A.在激光共聚焦培养皿(35mm)接种8×104个HepG2细胞。
B.培养24h后，用pH 7.4的PBS溶液小心洗涤三遍。
C.在含有20μg/mL-1的Cep@Gli-MOF培养基里孵育3h后，移除培养基，用pH 7.4的PBS溶液小心洗涤三遍。
D.用50nM的ER-Tracker在37℃下孵育60min后，用pH 7.4的PBS溶液小心洗涤三遍。
D.加入4％多聚甲醛在室温下固定15min。随后用4’,6-二脒基-2-苯基吲哚(DAPI)染色细胞核15min。最后用PBS润洗后，置于激光共聚焦下观察。
E.由图3可以看到，装载千金藤素的金属框架Cep@Gli-MOF能靶向富集至肿瘤细胞内质网。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点，对于本领域技术人员而言，显然本发明不限于上述示范性实施例的细节，而且在不背离本发明的精神或基本特征的情况下，能够以其他的具体形式实现本发明。因此，无论从哪一点来看，均应将实施例看作是示范性的，而且是非限制性的，本发明的范围由所附权利要求而不是上述说明限定，因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。不应将权利要求中的任何附图标记视为限制所涉及的权利要求。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
Claims (6)
1.一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于，其方法步骤包括如下：
步骤S1：通过一锅法制备装载有千金藤素的铁基金属框架材料，将FeCl3/6H2O溶液、TCPP溶液和苯甲酸相互混匀后，Cep溶液缓慢滴加到其中，得到反应液A；反应液A处理后在室温下真空干燥，得到固体粉末产品Cep@MOF；
步骤S2：通过派派堆积效应，将靶向配体格列本脲修饰到装载有千金藤素的铁基金属框架材料表面，通过将Cep@MOF溶液和格列本脲搅拌反应；反应完后，离心，用DMF清洗并真空干燥，得到固体粉末产品Cep@Gli-MOF。
2.根据权利要求1所述一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于：所述铁基金属框架材料，是以铁离子为金属结点的金属框架材料MOFs。
3.根据权利要求1所述一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于：所述步骤S2中制得的Cep@Gli-MOF通过扫描电镜(SEM)、透射电镜(TEM)、紫外-可见吸收光谱分析、红外光谱分析和动态光散射技术来表征粒径的分布，从而得知制得的Cep@Gli-MOF为分布均匀的球形纳米颗粒，粒径为55nm。
4.根据权利要求1所述一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于：所述步骤S1中反液A处理方法为将反应液A在90℃下回流加热5h，待反应完后，离心，用DMF洗三次。
5.根据权利要求1所述一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于：所述步骤S2中用DMF清洗次数为三次，在温度23℃±2℃下真空干燥。
6.根据权利要求1所述一种靶向激活内质网应激的金属框架Cep@Gli-MOF的制备方法，其特征在于：所述步骤S2中Cep@MOF溶液和格列本脲在温度23℃±2℃下搅拌，搅拌时间为4h。
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