CN116327983A - 一种奶酪形多孔结构纳米氧化锰造影剂的制备方法及应用 - Google Patents
一种奶酪形多孔结构纳米氧化锰造影剂的制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种奶酪形多孔结构纳米氧化锰造影剂的制备方法及应用,其具体制备过程为:将锰盐、三辛基氧膦和油酸钠混合后加入到高沸点溶剂中,在惰性气体氛围中加热回流反应,反应结束后冷却至室温,加入弱极性有机溶剂溶解后离心分离,再加入非极性溶剂和含有多巴胺聚乙二醇的水溶液搅拌,收集水相溶液,离心分离得到表面修饰多巴胺聚乙二醇的奶酪形多孔结构纳米氧化锰造影剂。本发明制备过程简单,制得的纳米氧化锰造影剂结构稳定,在磁共振成像中具有较高的纵向弛豫率。
Description
技术领域
本发明属于医学影像造影剂技术领域,具体涉及一种奶酪形多孔结构纳米氧化锰造影剂的制备方法及应用。
背景技术
磁共振成像是一项广泛应用于医学诊断领域的影像技术。造影剂能够加速原子核的弛豫速率,进而提高磁共振成像的灵敏度和诊断的可靠性。目前临床应用的造影剂主要有两类,一类是顺磁性钆离子配合物,如马根维显(Magnevist)和普美显(Primovist),另一类是超顺磁氧化铁纳米颗粒,如菲立磁(Feridex)。然而钆离子具有毒性,被警示有引起肾毒性纤维化的风险;超顺磁氧化铁纳米颗粒则主要加强横向弛豫,使病灶部位呈现暗信号,不易分辨(E. Terreno, D. D. Castelli, A. Viale, S. Aime, Chem. Rev., 2010,110, 3019)。随着社会和经济的发展,人们对造影剂的性能提出了更高的要求。
纳米技术的发展为造影剂的创新应用提供了新的变革机遇。由于锰(II)离子的半满d层轨道,基于锰元素的纳米材料在造影剂应用中具有巨大的潜力。其中氧化锰(MnO)纳米材料由于合成简便,稳定性好,因而获得广泛的关注。然而一般的氧化锰纳米颗粒表现为均一的球状形貌,比表面积小,纵向弛豫率不够理想(J. Huang, J. Xie, K. Chen, L.Bu, S. Lee, Z. Cheng, X. Li, X. Chen, Chem. Comm., 2010, 46, 6684)。如何提高氧化锰纳米材料的比表面积,获得高弛豫率的纳米氧化锰造影剂,对于磁共振成像具有重要意义。
发明内容
本发明解决的技术问题是提供了一种奶酪形多孔结构纳米氧化锰造影剂的制备方法,该方法制备的纳米氧化锰造影剂在磁共振成像中具有较高的弛豫率。
本发明为解决上述技术问题采用如下技术方案,一种奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于具体过程为:将锰盐、三辛基氧膦和油酸钠混合后加入到高沸点溶剂中,其中锰盐为油酸锰或乙酰丙酮锰中的一种或多种,高沸点溶剂为十八烯、苄醚、油酸或油胺中的一种或多种,在惰性气体氛围中加热回流反应,反应结束后冷却至室温,加入弱极性有机溶剂溶解后离心分离,再加入非极性溶剂和含有多巴胺聚乙二醇的水溶液搅拌,收集水相溶液,离心分离得到表面修饰多巴胺聚乙二醇的奶酪形多孔结构纳米氧化锰造影剂,其粒径为30~300nm。
进一步限定,所述弱极性有机溶剂为甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、乙腈或丙酮中的一种或多种。
进一步限定,所述非极性溶剂为正己烷、环己烷、四氯化碳、氯仿、二氯甲烷、苯或甲苯中的一种或多种。
进一步限定,所述多巴胺聚乙二醇包括以多巴胺为代表的具有邻苯二酚结构的聚乙二醇聚合物,平均分子量(Mw)为200~50000Da。
进一步限定,所述含有多巴胺聚乙二醇的水溶液中多巴胺聚乙二醇的浓度为0.01~50mg/mL。
本发明所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于具体步骤为:
步骤S1,将前驱体锰盐、三辛基氧膦和油酸钠按摩尔比10~200:1~5:1混合后加入到高沸点溶剂中,其中锰盐为油酸锰或乙酰丙酮锰,溶液中前驱体的总浓度为0.02~0.1g/mL,在惰性气体氛围中加热至240~280℃回流反应;
步骤S2,将步骤S1反应结束后的反应液冷却至室温,加入弱极性有机溶剂,离心,弃去上清液;
步骤S3,将步骤S2得到的产物加入非极性溶剂溶解,再加入含有多巴胺聚乙二醇的水溶液搅拌,收集水相溶液,离心处理,弃去上清液得到表面修饰多巴胺聚乙二醇的奶酪形多孔结构纳米氧化锰造影剂。
本发明所述的奶酪形多孔结构纳米氧化锰材料作为磁共振成像造影剂的应用。
进一步限定,所述奶酪形多孔结构纳米氧化锰造影剂在肿瘤部位造影中的应用。
进一步限定,所述奶酪形多孔结构纳米氧化锰造影剂在肿瘤部位造影中的应用,奶酪形多孔结构使造影剂具有较大的比表面积,能够与更多的水分子发生配位,加快水分子纵向弛豫,在磁共振成像中具有较高的纵向弛豫率,增强成像信号。
与目前广泛研究的球形纳米氧化锰造影剂相比,本发明制备的奶酪形多孔结构纳米氧化锰造影剂具有以下优点和有益效果:
1)以前驱体为原料通过高温热分解法合成的奶酪形多孔结构纳米氧化锰颗粒,不需添加其它表面活性剂,具有操作简单,粒径可调控等特点,易于放大生产;
2)纳米氧化锰造影剂经过多巴胺聚乙二醇进行表面修饰,多巴胺的邻苯二酚基团与锰元素结合牢固,聚乙二醇具有生物相容性好的特点,该纳米造影剂可直接应用于生物医学领域;
3)奶酪形多孔结构使该纳米氧化锰造影剂具有较大的比表面积,能够与更多的水分子发生配位,在磁共振成像中具有较高的纵向弛豫率。
附图说明
图1为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的设计原理示意图。
图2为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的扫描电镜图。
图3为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的X射线粉末衍射图谱及标准卡片JCPDS#75-0257;横坐标为2Theta角度,纵坐标为相对强度。
图4为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的氮气吸-脱附等温线(a)和表面积拟合线(b)。
图5为不同浓度的实施例1制备的奶酪形多孔结构纳米氧化锰造影剂在1T磁场下的纵向弛豫加权磁共振成像(a)和纵向弛豫率(b);b图中横坐标为造影剂的锰元素浓度,纵坐标为纵向弛豫率(1/T1)。
图6为荷瘤小鼠肿瘤部位的纵向弛豫加权磁共振成像;a)注射造影剂前;b)为经尾静脉注射实施例1制备的奶酪形多孔结构纳米氧化锰造影剂之后2h。
图7为实施例2制备的奶酪形多孔结构纳米氧化锰造影剂的扫描电镜图。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
粒径为80nm的奶酪形多孔结构纳米氧化锰造影剂的制备:
取1.2g油酸锰、25.4mg三辛基氧膦和15mg油酸钠置于圆底烧瓶中,加入25mL十八烯,将反应瓶中的空气置换成氮气。在磁子搅拌下加热至270℃并保持回流2h后停止反应,冷却至室温。将反应液吸出,加入60mL异丙醇,8000rpm离心10min,弃去上清液,加入10mL正己烷溶解沉淀。将此正己烷溶液加入到含有2mg/mL多巴胺聚乙二醇(Mw = 3000)的水溶液中,超声15min,收集水相溶液,8000rpm离心10min,弃去上清液,所得沉淀即粒径为80nm的奶酪形多孔结构纳米氧化锰造影剂。
将所得的80nm的奶酪形多孔结构纳米氧化锰造影剂溶解于磷酸盐缓冲液中,经尾静脉注射到荷瘤小鼠体内,注射剂量4mg/kg。注射2h后进行纵向弛豫加权磁共振成像。
图2为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的扫描电镜图,图2表明所制备的造影剂平均粒径80nm,表面具有奶酪形多孔结构;图3为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的X射线粉末衍射图谱及标准卡片JCPDS#75-0257作为对比,图3表明实施例1制备的造影剂无机材料为纳米氧化锰。
图4为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂的氮气吸-脱附等温线(a)和表面积拟合线(b),图4结果表明实施例1制备的奶酪形多孔结构纳米氧化锰造影剂具有较高的比表面积119.8221m2/g。
图5为实施例1制备的奶酪形多孔结构纳米氧化锰造影剂在不同浓度下的纵向弛豫加权磁共振成像(a)和纵向弛豫率(b),图5结果表明实施例1制备的奶酪形多孔结构纳米氧化锰造影剂具有较好的成像效果和较高的弛豫率21.76mM-1s-1。
图6为荷瘤小鼠肿瘤部位的纵向弛豫加权磁共振成像。通过将注射造影剂前后图像对比,肿瘤部位在注射造影剂后信号明显提高,说明实施例1制备的奶酪形多孔结构纳米氧化锰造影剂能够有效提高肿瘤部位的信号强度,增强造影效果。
实施例2
粒径为190nm的奶酪形多孔结构纳米氧化锰造影剂的制备:
取2.9g乙酰丙酮锰、265mg三辛基氧膦和50mg油酸钠置于圆底烧瓶中,加入50mL十八烯、10mL苄醚和2mL油酸,将反应瓶中的空气置换成氩气。在磁子搅拌下加热至260℃并保持回流3h后停止反应,冷却至室温。将反应液吸出,加入100mL乙腈,10000rpm离心8min,弃去上清液,加入20mL二氯甲烷溶解沉淀。将此二氯甲烷溶液加入到含有5mg/mL多巴胺聚乙二醇(Mw=10000)的水溶液中,搅拌30min,收集水相溶液,9000rpm离心8min,弃去上清液,所得沉淀即粒径为190nm的奶酪形多孔结构纳米氧化锰造影剂。
图7为实施例2制备的奶酪形多孔结构纳米氧化锰造影剂的扫描电镜图。
以上显示和描述了本发明的基本原理,主要特征和优点,在不脱离本发明精神和范围的前提下,本发明还有各种变化和改进,这些变化和改进都落入要求保护的本发明的范围。
Claims (9)
1.一种奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于具体过程为:将锰盐、三辛基氧膦和油酸钠混合后加入到高沸点溶剂中,其中锰盐为油酸锰或乙酰丙酮锰中的一种或多种,高沸点溶剂为十八烯、苄醚、油酸或油胺中的一种或多种,在惰性气体氛围中加热回流反应,反应结束后冷却至室温,加入弱极性有机溶剂溶解后离心分离,再加入非极性溶剂和含有多巴胺聚乙二醇的水溶液搅拌,收集水相溶液,离心分离得到表面修饰多巴胺聚乙二醇的奶酪形多孔结构纳米氧化锰造影剂,其粒径为30~300nm。
2.根据权利要求1所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于:所述弱极性有机溶剂为甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、乙腈或丙酮中的一种或多种。
3.根据权利要求1所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于:所述非极性溶剂为正己烷、环己烷、四氯化碳、氯仿、二氯甲烷、苯或甲苯中的一种或多种。
4.根据权利要求1所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于:所述多巴胺聚乙二醇包括以多巴胺为代表的具有邻苯二酚结构的聚乙二醇聚合物,平均分子量为200~50000Da。
5.根据权利要求1所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于:所述含有多巴胺聚乙二醇的水溶液中多巴胺聚乙二醇的浓度为0.01~50mg/mL。
6.根据权利要求1所述的奶酪形多孔结构纳米氧化锰造影剂的制备方法,其特征在于具体步骤为:
步骤S1,将前驱体锰盐、三辛基氧膦和油酸钠按摩尔比10~200:1~5:1混合后加入到高沸点溶剂中,其中锰盐为油酸锰或乙酰丙酮锰,溶液中前驱体的总浓度为0.02~0.1g/mL,在惰性气体氛围中加热至240~280℃回流反应;
步骤S2,将步骤S1反应结束后的反应液冷却至室温,加入弱极性有机溶剂,离心,弃去上清液;
步骤S3,将步骤S2得到的产物加入非极性溶剂溶解,再加入含有多巴胺聚乙二醇的水溶液搅拌,收集水相溶液,离心处理,弃去上清液得到表面修饰多巴胺聚乙二醇的奶酪形多孔结构纳米氧化锰造影剂。
7.根据权利要求1~6中任意一项所述的方法制备的奶酪形多孔结构纳米氧化锰材料作为磁共振成像造影剂的应用。
8.根据权利要求7所述的应用,其特征在于:所述奶酪形多孔结构纳米氧化锰造影剂在肿瘤部位造影中的应用。
9.根据权利要求8所述的应用,其特征在于:所述奶酪形多孔结构纳米氧化锰造影剂在肿瘤部位成像造影中的应用,奶酪形多孔结构具有较大的比表面积,能够与更多的水分子发生配位,加快水分子的纵向弛豫,在磁共振成像中具有较高的纵向弛豫率,增强成像信号。
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