CN110624117B - 具有氧化还原响应的t1/t2双模态纳米造影剂空心mco及其制备方法和应用 - Google Patents
具有氧化还原响应的t1/t2双模态纳米造影剂空心mco及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法。其步骤为：通过控制不同的反应条件制备不同尺寸的空心纳米MCO粒子,通过氨基在空心纳米MCO粒子表面修饰上氨基化聚乙二醇，得到具有优异生物相容性和氧化还原响应的T1/T2双模态一体的空心纳米MCO粒子。本发明合成步骤简单，操作方便，可以改变加工条件来改变空心纳米MCO尺寸，此外空心纳米MCO本身具有较好的生物相容性，同时，空心纳米MCO具有优秀的氧化还原响应效果，从而使得空心纳米MCO能够在癌症环境分解释放包裹药物，定向杀死癌细胞。空心纳米MCO也在T1/T2双模态生物成像材料方面展现出广阔的应用前景。
Description
技术领域
本发明属于新型核磁共振造影剂的制备技术领域，涉及一种具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO及其制备方法和应用。
背景技术
纳米材料由于其较小的尺寸而致使其具有优异的表面效应如尺寸效应、优异的生物相容性和生物吸收代谢等特性。
癌症，是正常细胞突变为可无限增殖并向其他部位扩散的一类异常细胞所引起的疾病。一般而言，正常细胞的谷胱甘肽(GSH)浓度在10nM左右，而癌细胞周围的谷胱甘肽浓度高达10mM。通过设计环境响应型功能材料特别是对于谷胱甘肽的氧化还原响应的纳米材料，有利于为智能药物传输奠定良好基础。磁共振成像技术(magnetic resonanceimaging，MRI)可以诊断出早期肿瘤，还可以在体内直接监测疾病的病源、病变过程及一系列的病理和生理变化，使其在医学检测中迅速发展，也是近几年来国内外学者研究的热点之一(Smith B R,Gambhir S S.Nanomaterials for in vivo imaging[J].Chemicalreviews,2017,117(3):901-986；Dai Y,Xu C,Sun X,et al.Nanoparticle designstrategies for enhanced anticancer therapy by exploiting the tumourmicroenvironment[J].Chemical Society Reviews,2017,46(12):3830-3852.)。造影剂通过注射或者口服方式进入人体，用于增强成像效果的化学材料。在此选用设计合成的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO，具有合成步骤简单，操作方便，生物相容性好等优点。目前，虽然制备具有T1/T2双模态的纳米粒子的方法有很多，但是这些方法过程复杂、参数精细。而我们一步合成生物相容性好的空心MCO，操作简单，重复性高，无疑是一种高效的制备空心MCO的方法。
发明内容
本发明的目的是提供一种具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO(钴锰氧)的制备方法，简单操作即可合成生物相容性好的空心MCO。
本发明的技术方案：一种具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，向氯化钴与聚丙烯酸(PAA)的溶液中先后加入硼氢化钠(NaBH4)和高锰酸钾(KMnO4)溶液反应得到PAA修饰的空心纳米MCO，将PAA修饰的空心纳米MCO与氨基化聚乙二醇(PEG-NH2)反应，得到氧化还原响应的T1/T2双模态纳米造影剂空心MCO。
优选的，包括如下步骤：
A、称取2mg～20mg的氯化钴，用20ml～200ml的水溶解配制成溶液，随后将溶液搅拌20min-60min；
B、向10mg～20mg的氯化钴溶液中加入20mg～80mg的PAA试剂中，室温搅拌反应60min～300min，然后加入4mg-8mg NaBH4，搅拌得到PAA修饰的纳米钴；
C、将步骤B中获得PAA修饰的纳米钴溶液取10mg～20mg与10mg～40mg KMnO4室温搅拌反应10min～20min，离心得到沉淀，去离子水洗涤，得到PAA修饰的空心纳米MCO。
D、将步骤C中获得PAA修饰的空心纳米MCO溶液取20mg～40mg与80mg～160mg PEG-NH2室温搅拌反应2h～4h，离心得到沉淀，去离子水洗涤，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO。
优选的，本发明步骤A中，所述氯化钴的质量为15mg；用水的体积为150ml；室温反应时间为30min。
优选的，本发明步骤B中，所述氯化钴溶液的质量为15mg；PAA试剂的质量为40mg；室温反应时间为120min；NaBH4的质量为6mg；室温反应时间为2min。
优选的，本发明步骤C中，所述PAA修饰的纳米钴溶液的质量为20mg；KMnO4试剂的质量为40mg；室温反应时间为20min。
优选的，所述PAA修饰的空心纳米MCO溶液为40mg；PEG-NH2的质量为100mg；室温反应时间为2h。
本发明还公开了上述的T1/T2双模态纳米造影剂空心MCO的制备方法制得的T1/T2双模态纳米造影剂空心MCO。
本发明还公开了上述的T1/T2双模态纳米造影剂空心MCO在声光成像或核磁共振成像的造影剂中的应用。
本发明通过控制不同的反应条件(比如:PAA含量和反应时间)制备不同尺寸的空心纳米MCO粒子,通过氨基在空心纳米MCO粒子表面修饰上聚乙二醇，得到具有优异生物相容性和氧化还原响应的T1/T2双模态一体的空心纳米MCO粒子。本发明合成步骤简单，操作方便，可以改变加工条件来改变空心纳米MCO尺寸，此外空心纳米MCO本身具有较好的生物相容性，同时，空心纳米MCO具有优秀的氧化还原响应效果，可与癌症周围GSH发生氧化还原反应，从而使得空心纳米MCO能够在癌症环境分解释放包裹药物，定向杀死癌细胞。空心纳米MCO也在T1/T2双模态生物成像材料方面展现出广阔的应用前景。本发明具有以下有益效果：
1、本发明的工艺操作简单，尺寸均匀且可重复性高，能满足实验室和工业需求。
2、本发明制备的空心纳米MCO具备生物相容性好、无毒害作用的优点。
3、本发明可以通过改变PAA含量和反应时间控制得到不同尺寸的空心纳米MCO。
4、本发明制备的空心纳米MCO具有氧化还原响应的医药载体和造影剂。
附图说明
图1是实施例1制备的空心纳米MCO的扫描和透射电子显微镜照片。
图2是实施例2制备的空心纳米MCO的扫描和透射电子显微镜照片。
图3是实施例3制备的空心纳米MCO的扫描和透射电子显微镜照片。
图4是实施例4制备的空心纳米MCO的扫描和透射电子显微镜照片。
图5是实施例3制备的空心纳米MCO在有无谷胱甘肽(GSH)条件下的T1弛豫率曲线(r1＝2.24和3.43mM-1s-1)，插入图为T1造影成像图。
图6是实施例3制备的空心纳米MCO在有无GSH条件下的T2弛豫率曲线(r2＝32.51和110.70mM-1s-1)，插入图为T2造影成像图。
图7是MCO对阿霉素(DOX)的负载曲线。
具体实施方式
下面结合附图对本发明的技术方案作进一步的说明，但并不局限于此，凡是对本发明技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，均应涵盖在本发明的保护范围中。
实施例1：
称取2mg的氯化钴，用20ml的水溶解配制成溶液，随后将溶液搅拌20min；量取10mg的氯化钴溶液，并向其中加入20mg的PAA试剂中，室温搅拌反应60min，然后加入4mg NaBH4，搅拌反应2min得到PAA修饰的纳米钴；量取PAA修饰的纳米钴溶液10mg与20mg KMnO4室温搅拌反应10min，离心得到沉淀，去离子水洗涤三次，得到PAA修饰的空心纳米MCO。将PAA修饰的空心纳米MCO溶液取20mg与80mg PEG-NH2室温搅拌反应2h，离心得到沉淀，去离子水洗涤三次，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO,尺寸在50.5±6.4nm。
实施例2：
称取2mg的氯化钴，用100ml的水溶解配制成溶液，随后将溶液搅拌30min；量取15mg的氯化钴溶液，并向其中加入40mg的PAA试剂中，室温搅拌反应90min，然后加入5mgNaBH4，搅拌反应3min得到PAA修饰的纳米钴；量取PAA修饰的纳米钴溶液20mg与30mg KMnO4室温搅拌反应15min，离心得到沉淀，去离子水洗涤三次，得到PAA修饰的空心纳米MCO。将PAA修饰的空心纳米MCO溶液取30mg与100mg PEG-NH2室温搅拌反应2.5h，离心得到沉淀，去离子水洗涤三次，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO,尺寸在67.5±9.4nm。
实施例3：
称取2mg的氯化钴，用150ml的水溶解配制成溶液，随后将溶液搅拌30min；量取15mg的氯化钴溶液，并向其中加入40mg的PAA试剂中，室温搅拌反应120min，然后加入6mgNaBH4，搅拌反应2min得到PAA修饰的纳米钴；量取PAA修饰的纳米钴溶液20mg与40mg KMnO4室温搅拌反应20min，离心得到沉淀，去离子水洗涤三次，得到PAA修饰的空心纳米MCO。将PAA修饰的空心纳米MCO溶液取40mg与100mg PEG-NH2室温搅拌反应2h，离心得到沉淀，去离子水洗涤三次，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO,尺寸在95±7.9nm。
实施例4：
称取2mg的氯化钴，用200ml的水溶解配制成溶液，随后将溶液搅拌60min；量取20mg的氯化钴溶液，并向其中加入80mg的PAA试剂中，室温搅拌反应300min，然后加入8mgNaBH4，搅拌反应4min得到PAA修饰的纳米钴；量取PAA修饰的纳米钴溶液15mg与40mg KMnO4室温搅拌反应20min，离心得到沉淀，去离子水洗涤三次，得到PAA修饰的空心纳米MCO。将PAA修饰的空心纳米MCO溶液取40mg与160mg PEG-NH2室温搅拌反应4h，离心得到沉淀，去离子水洗涤三次，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO,尺寸在286±47.2nm。
实施例5：
向氯化钴溶液中加入80mg的PAA试剂，其它条件与实施例1相同，最终得到的空心MCO尺寸在85.2±6.9nm。
实施例6：
加入8mg NaBH4，其它条件与实施例1相同，最终得到的空心MCO尺寸在101.2±5.3nm。
实施例7：
量取PAA修饰的纳米钴溶液10mg与40mg KMnO4室温搅拌反应，其它条件与实施例1相同，最终得到的空心MCO尺寸在92.3±3.2nm。
实施例8：
将PAA修饰的空心纳米MCO溶液取20mg与120mg PEG-NH2室温搅拌反应，其它条件与实施例1相同，最终得到的空心MCO尺寸在58.5±6.9nm。
实施例9：
将PAA修饰的空心纳米MCO溶液取20mg与160mg PEG-NH2室温搅拌反应，其它条件与实施例1相同，最终得到的空心MCO尺寸在67.2±2.8nm。
实施例10：
向氯化钴溶液中加入20mg的PAA试剂，其它条件与实施例4相同，最终得到的空心MCO尺寸在102.3±5.4nm。
实施例11：
加入4mg NaBH4，其它条件与实施例4相同，最终得到的空心MCO尺寸在125.6±5.6nm。
实施例12：
量取PAA修饰的纳米钴溶液15mg与10mg KMnO4室温搅拌反应，其它条件与实施例4相同，最终得到的空心MCO尺寸在110.5±8.6nm。
实施例13：
将PAA修饰的空心纳米MCO溶液取40mg与80mg PEG-NH2室温搅拌反应，其它条件与实施例4相同，最终得到的空心MCO尺寸在253.6±4.3nm。
实施例14：
将PAA修饰的空心纳米MCO溶液取20mg与160mg PEG-NH2室温搅拌反应，其它条件与实施例4相同，最终得到的空心MCO尺寸在220.4±9.1nm。
实施例15-20：
将实施例1、5-9中，配制氯化钴溶液时称取氯化钴量均改为15mg，其它条件不变，相应的最终得到的空心MCO尺寸在分别是320.4±2.6,440.5±7.9,510.2±9.1,480.3±4.2,126.9±4.2,142.3±6.1nm。
实施例21-26：
将实施例4、10-14中，配制氯化钴溶液时称取氯化钴量均改为20mg，其它条件不变，相应的最终得到的空心MCO尺寸在分别是425.4±5.4,552.5±4.2,765.2±2.3,627.3±6.5,224.6±9.2,259.7±2.9nm。
Claims (8)
1.一种具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于：在氯化钴溶液中加入PAA，再先后加入NaBH4和KMnO4溶液反应得到PAA修饰的空心纳米MCO，PAA修饰的空心纳米MCO加入PEG-NH2进行反应，得到氧化还原响应的T1/T2双模态纳米造影剂空心MCO。
2.根据权利要求1所述的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于具体步骤为：
A、称取2mg~20mg的氯化钴，用20ml~200ml的水溶解配制成溶液，随后将溶液搅拌20min-60min；
B、向10mg~20mg的氯化钴溶液中加入20mg~80mg的PAA试剂，室温搅拌反应60min~300min，然后加入4mg-8mg NaBH4，搅拌得到PAA修饰的纳米钴；
C、将步骤B中获得PAA修饰的纳米钴溶液取10mg~20mg与10mg~40mg KMnO4室温搅拌反应10min~20min，离心得到沉淀，去离子水洗涤，得到PAA修饰的空心纳米MCO；
D、将步骤C中获得PAA修饰的空心纳米MCO溶液取20mg~40mg与80mg~160mg PEG-NH2室温搅拌反应2h~4h，离心得到沉淀，去离子水洗涤，得到具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO。
3.根据权利要求2所述的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于：步骤A中氯化钴的质量为15mg；用水的体积为150ml；室温反应时间为30min。
4.根据权利要求3所述的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于：步骤B中氯化钴溶液的质量为15mg； PAA试剂的质量为40mg；室温反应时间为120min；NaBH4的质量为6mg；室温反应时间为2min。
5.根据权利要求4所述的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于：步骤C中PAA修饰的纳米钴溶液的质量为20mg； KMnO4试剂的质量为40mg；室温反应时间为20min。
6.根据权利要求5所述的具有氧化还原响应的T1/T2双模态纳米造影剂空心MCO的制备方法，其特征在于：步骤D中PAA修饰的空心纳米MCO溶液为40mg； PEG-NH2的质量为100mg；室温反应时间为2h。
7.权利要求1-6中任一项所述的T1/T2双模态纳米造影剂空心MCO的制备方法制得的T1/T2双模态纳米造影剂空心MCO。
8.权利要求7所述的T1/T2双模态纳米造影剂空心MCO在制备声光成像或核磁共振成像的造影剂中的应用。
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