CN104043138A - 稀土基纳米颗粒磁共振造影剂及其制备方法 - Google Patents

稀土基纳米颗粒磁共振造影剂及其制备方法 Download PDF

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CN104043138A
CN104043138A CN201410233943.9A CN201410233943A CN104043138A CN 104043138 A CN104043138 A CN 104043138A CN 201410233943 A CN201410233943 A CN 201410233943A CN 104043138 A CN104043138 A CN 104043138A
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rare earth
contrast agent
magnetic resonance
resonance contrast
particle
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孙聆东
严纯华
郑晓宇
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Peking University
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Priority to JP2016569952A priority patent/JP2017518993A/ja
Priority to US15/314,339 priority patent/US20170196997A1/en
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Abstract

本发明涉及一种稀土基纳米颗粒磁共振造影剂及其制备方法。该稀土基纳米颗粒磁共振造影剂是表面包覆亲水性配体的稀土基无机纳米颗粒，首先通过高温油相反应获得稀土基纳米颗粒，然后在其表面包覆亲水性分子后得到稀土基纳米颗粒磁共振造影剂。本发明的磁共振造影剂与现有临床造影剂相比，弛豫率大大提高，成像效果好，所需注射剂量低，且体内停留时间较长。此外，无机纳米颗粒的刚性结构可有效降低钆离子游离可能。本发明制备方法简单、重复性较好、性质稳定，易于实现临床商业化应用。

Description

稀土基纳米颗粒磁共振造影剂及其制备方法
技术领域
本发明涉及一种稀土基纳米颗粒磁共振造影剂及其制备方法，属于纳米材料技术领域。
背景技术
磁共振成像(Magnetic Resonance Imaging,MRI)是医学诊断与分子成像领域中的一项重要技术，具有组织分辨率高、成像参数多、对人体无辐射损伤等优点。但由于MRI技术灵敏度较低，临床上常采用造影剂(Contrast Agents)来提高成像对比度和图像质量。造影剂可根据横、纵向弛豫率的比值高低分为两类：使局部组织变亮的T1造影剂和使局部组织变暗的T2造影剂。稀土离子具有未充满的4f电子层，因此具有独特的光、电、磁学特性，在磁共振T1与T2造影方面都具有重要的应用价值。
在T1造影剂方面，三价的钆离子(Gd3+)具有最多的未成对电子数，且电子自旋弛豫时间长，可以有效缩短纵向弛豫时间来增加图像亮度，因此被认为是T1造影剂的最佳选择。为了降低游离的钆离子带来毒性的风险，当前应用最为广泛的T1造影剂是含钆的顺磁性螯合物，以期通过螯合的方式降低其游离的可能。然而，该类造影剂通常弛豫率较低，造影效果有限，且所需剂量大，对于正常组织仍有一定的威胁。此外，由于该类造影剂属于小分子，体内停留时间短，无法保证长时间的诊断效果。
在T2造影剂方面，具有超顺磁性的氧化铁纳米颗粒造影剂已经实现了商业化，但遗憾的是，此类造影剂在较低的磁场强度下(1.5T)便已达到饱和磁化强度，在更高磁场强度下的造影效果较差(NaDyF4Nanoparticles as T-2Contrast Agents for Ultrahigh Field MagneticResonance Imaging,Frank C.J.M.van Veggel,et al.J.Phys.Chem.Lett.2012,3,524-529)。而稀土离子(如铽Tb3+、镝Dy3+、钬Ho3+、铒Er3+)具有较大的磁矩以及较短的电子自旋弛豫时间，有望满足高磁场强度下的造影需求。
综上所述，稀土基的无机纳米颗粒有望成为新一代高效的磁共振造影剂，因为单个颗粒包含大量的稀土离子，可产生更加显著的信号增强，且无机纳米结构的刚性骨架可以降低稀土离子游离的可能性。又由于纳米颗粒的尺寸大于螯合物，其体内循环时间较长。此外，无机纳米结构的表面易于修饰功能性基团以达到主动靶向、多模式成像等目的。因此，稀土基纳米颗粒磁共振造影剂的开发与利用对于提高诊断的准确性及造影剂的安全性具有重要的意义。
发明内容
本发明提出了一种稀土基纳米颗粒磁共振造影剂及其制备方法，该磁共振造影剂具有弛豫率高、注射剂量小、体内循环时间较长、稀土离子游离可能性低等特点。
本发明的稀土基纳米颗粒磁共振造影剂指的是表面包覆亲水性配体的稀土基无机纳米颗粒。本发明首先通过高温油相反应获得稀土基纳米颗粒，然后在其表面包覆亲水性分子后得到稀土基纳米颗粒磁共振造影剂。
本发明的稀土基纳米颗粒磁共振造影剂中稀土元素(RE)包括镧(La)、铈(Ce)、镨(Pr)、钕(Nd)、钐(Sm)、铕(Eu)、钆(Gd)、铽(Tb)、镝(Dy)、钬(Ho)、铒(Er)、铥(Tm)、镱(Yb)、镥(Lu)、钪(Sc)和钇(Y)中的一种或几种。
本发明的稀土基纳米颗粒磁共振造影剂中稀土基纳米颗粒的组成是MaREObXc，其中RE代表稀土元素，M代表碱金属或碱土金属，X代表氟或氯，0≤a≤1，0≤b≤1.5，0≤c≤4。此外，稀土基纳米颗粒还可以是以MaREObXc为基质进行掺杂的无机化合物，进行掺杂的作用是赋予其发光性质或调控其磁性。
本发明的稀土基纳米颗粒磁共振造影剂的表面包覆配体可以采用下列中的一种或多种：柠檬酸、半胱氨酸等亲水性小分子，以及聚乙烯醇、聚乙烯亚胺、聚乙烯吡咯烷酮、聚丙烯酸等亲水性高分子。
本发明提出一种稀土基纳米颗粒磁共振造影剂的制备方法，其步骤为：
1)在高沸点有机溶剂中，加入一定量的稀土前驱体或者稀土前驱体与非稀土前驱体的混合物，得到溶液A；
2)对溶液A抽真空以除去水分，然后在惰性气体保护下升温至250-340℃，维持15min-24h，然后冷却至室温，得到溶胶B；
3)对溶胶B进行离心分离，对所得沉淀物进行洗涤，再对沉淀物的表面进行亲水性配体的包覆；
4)将包覆后的颗粒分散于溶剂中，即得到造影剂。
其中，步骤1)中前驱体与溶剂摩尔比的优选范围是1:20-1:200，前驱体中稀土前驱体是必须要加入的，而非稀土前驱体是否要加入取决于目标产物的组成；步骤2)优选在100-140℃下进行所述抽真空；步骤3)优选采用大量乙醇进行洗涤，洗涤方式优选为离心洗涤，洗涤次数优选为2-6次；步骤4)所述溶剂优选为水或生理盐水。
本发明中的高沸点有机溶剂指油酸、亚油酸、油胺、十八烯、十六胺和十八胺中的一种或多种组成的混合溶剂。
本发明中的稀土前驱体是下列中的一种或多种的混合：稀土的氢氧化物、草酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、乙酰丙酮盐、苯基乙酰丙酮盐。
本发明中的非稀土前驱体是下列中的一种或多种的混合：碱金属与碱土金属的氟化物、氢氧化物、草酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、乙酰丙酮盐、苯基乙酰丙酮盐。
本发明的稀土基纳米颗粒磁共振造影剂的制备方法中，稀土基纳米颗粒可通过溶剂比例、前驱体投料量、反应温度、反应时间等参数调节纳米颗粒的组成、尺寸、形貌、晶化程度等；并可通过亲水性配体的表面包覆过程中水溶性分子的种类、投料量等调节造影剂的弛豫性质、生物相容性等。
本发明的稀土基纳米颗粒磁共振造影剂具有以下优点：
1.本发明的磁共振造影剂单个颗粒包含大量的稀土离子，可显著降低周围质子的弛豫时间；
2.本发明的磁共振造影剂尺寸大于螯合物，体内循环时间较长，可满足临床上长时间诊断的需要；
3.本发明的磁共振造影剂弛豫率较高，与临床常用造影剂相比可高出约十倍，同浓度条件下造影效果更好；
4.本发明的磁共振造影剂拥有无机纳米结构的刚性骨架，可减小稀土离子游离的可能，与螯合物相比更安全；
5.本发明的磁共振造影剂由于造影性能优异，所需剂量与当前临床常用造影剂相比可大幅减少，可进一步降低损伤正常组织的风险；
6.本发明的磁共振造影剂反应操作简单，易于控制，重复性良好，性质稳定。
附图说明
图1是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共振图像对比，所用扫描序列为T1加权序列，所用磁场强度为3T。
图2是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共振图像对比，所用扫描序列为T2加权序列，所用磁场强度为3T。
图3是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共振图像对比，所用扫描序列为ceMRA序列，所用磁场强度为3T。
图4是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共振图像对比，所用扫描序列为LAVA序列，所用磁场强度为3T。
图5是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂的弛豫率对比示意图，所用磁场强度为3T。
图6是稀土基纳米颗粒磁共振造影剂在不同磁场强度下的弛豫率对比。
具体实施方式
以下结合具体的实施方式，对本发明申请所述的稀土基纳米颗粒磁共振造影剂及其制备方法进行描述，目的是为了公众更好地理解所述的技术内容，而不是对所述技术内容的限制，事实上，在以相同或近似的原理对所述复合材料及其制备方法进行的改进，都在本发明申请所要求保护的技术方案之内。以下仅以50mL容量反应体系为例对实施方式进行说明，实际制备中可采用各物料同比例放大方式加以实施。
实施例一
Gd2O3纳米颗粒的合成：向油酸(4mL)、油胺(12mL)的混合溶剂中加入0.5mmol乙酰丙酮钆，惰性气体保护下加热至340℃，维持该温度15min，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到Gd2O3纳米颗粒。
实施例二
Pr2O3纳米颗粒的合成：向油酸(6mL)、油胺(12mL)的混合溶剂中加入0.5mmol乙酸镨，惰性气体保护下加热至340℃，维持该温度2h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到Pr2O3纳米颗粒。
实施例三
Er2O3纳米颗粒的合成：向油酸(6mL)、油胺(8mL)的混合溶剂中加入0.5mmol苯基乙酰丙酮铒，惰性气体保护下加热至310℃，维持该温度1h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到Er2O3纳米颗粒。
实施例四
Y2O3纳米颗粒的合成：向油酸(2mL)、油胺(3mL)与十八烯(5mL)的混合溶剂中加入0.5mmol氢氧化钇，惰性气体保护下加热至310℃，维持该温度1h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到Y2O3纳米颗粒。
实施例五
LaF3纳米颗粒的合成：向油酸(20mmol)与十八烯(20mmol)的混合溶剂中加入1mmol三氟乙酸镧与0.5mmol氟化锂，惰性气体保护下加热至260℃，维持该温度4h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到LaF3纳米颗粒。
实施例六
CeOF纳米颗粒的合成：向油酸(5mmol)与十六胺(35mmol)的混合溶剂中加入1mmol草酸铈，惰性气体保护下加热至320℃，维持该温度1h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到CeOF纳米颗粒。
实施例七
EuOCl纳米颗粒的合成：向油胺(20mmol)与十八烯(20mmol)的混合溶剂中加入1mmol三氯乙酸铕，惰性气体保护下加热至330℃，维持该温度1h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤两次，得到EuOCl纳米颗粒。
实施例八
NaDyF4:Yb,Er纳米颗粒的合成：向油酸(10mmol)、十八胺(10mmol)与十八烯(20mmol)的混合溶剂中加入0.78mmol三氟乙酸镝、0.20mmol三氟乙酸镱、0.02mmol三氟乙酸铒与1mmol三氟乙酸钠，惰性气体保护下加热至250℃，维持该温度0.5h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤四次，得到NaDyF4:Yb,Er纳米颗粒。
实施例九
LiTmF4纳米颗粒的合成：向油酸(20mmol)与十八烯(20mmol)的混合溶剂中加入1mmol三氟乙酸锂与1mmol三氟乙酸铥，惰性气体保护下加热至320℃，维持该温度15h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤六次，得到LiTmF4纳米颗粒。
实施例十
KYb2F7纳米颗粒的合成：向油酸(20mmol)与十八烯(20mmol)的混合溶剂中加入1mmol三氟乙酸钾与1mmol三氟乙酸镱，惰性气体保护下加热至310℃，维持该温度2h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤六次，得到KYb2F7纳米颗粒。
实施例十一
BaYF5纳米颗粒的合成：向亚油酸(10mmol)、油酸(10mmol)与十八胺(20mmol)的混合溶剂中加入1mmol草酸钡与1mmol三氟乙酸钇，惰性气体保护下加热至340℃，维持该温度24h，将反应液冷却至室温，向其中加入大量的乙醇，离心洗涤六次，得到BaYF5纳米颗粒。
实施例十二
颗粒表面包覆柠檬酸：将实施例一得到的Gd2O3纳米颗粒(0.1mmol)分散于5mL氯仿中，加入柠檬酸水溶液(n/n＝20)，室温下剧烈搅拌至少6h。取上层悬浊液体，加入大量乙醇离心，将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十三
颗粒表面包覆半胱氨酸：将实施例四得到的Y2O3纳米颗粒(0.1mmol)分散于5mL氯仿中，加入半胱氨酸水溶液(n/n＝30)，室温下剧烈搅拌至少6h。取上层悬浊液体，加入大量乙醇离心，将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十四
颗粒表面包覆聚乙烯醇：将实施例六得到的CeOF纳米颗粒(0.1mmol)分散于10mL环己烷中，加入10mL N,N-二甲基甲酰胺与50mg四氟硼酸亚硝鎓，剧烈搅拌不少于1h。取下层液体，加入大量甲苯离心，将所得沉淀再次溶于10mL N,N-二甲基甲酰胺，并加入聚乙烯醇50mg，搅拌不少于4h。然后向该溶液中加入大量丙酮，离心，将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十五
颗粒表面包覆聚乙烯亚胺：将实施例五得到的LaF3纳米颗粒(0.2mmol)分散于10mL环己烷中，加入10mL N,N-二甲基甲酰胺与50mg四氟硼酸亚硝鎓，剧烈搅拌不少于1h。取下层液体，加入大量甲苯离心，将所得沉淀再次溶于10mL N,N-二甲基甲酰胺，并加入聚乙烯亚胺50mg，搅拌不少于4h。然后向该溶液中加入大量丙酮，离心，将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十六
颗粒表面包覆聚乙烯吡咯烷酮：将实施例八得到的NaDyF4:Yb,Er纳米颗粒(0.2mmol)分散于10mL环己烷中，加入10mL N,N-二甲基甲酰胺与50mg四氟硼酸亚硝鎓，剧烈搅拌不少于1h。取下层液体，加入大量甲苯离心，将所得沉淀再次溶于10mL N,N-二甲基甲酰胺，并加入聚乙烯吡咯烷酮50mg，搅拌不少于4h。然后向该溶液中加入大量丙酮，离心，将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
图1-图4是实施例十二得到的稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共振图像对比，所用磁场强度均为3T。图1所用扫描序列为T1加权序列；图2所用扫描序列为T2加权序列；图3所用扫描序列为ceMRA序列；图4所用扫描序列为LAVA序列。由图1-图4可以看出，实施例十二得到的稀土基纳米颗粒磁共振造影剂在相同浓度的条件下，成像效果优于临床常用造影剂，且造影效果随浓度增加而显著提高(图1、图3、图4中图像越亮表示造影效果越好，图2中图像越暗表示造影效果越好)。需要说明的是，图1中稀土基纳米颗粒磁共振造影剂在较高浓度下图像变暗是由于“饱和效应”的存在，即此时T1造影效果已达到极限，而高浓度下T2造影效果将增强并部分抵消T1造影效果，该结果表明稀土基纳米颗粒磁共振造影剂在浓度低于临床常用造影剂的条件下即可达到相同的造影效果。
图5是实施例十二得到的稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂的弛豫率对比示意图，所用磁场强度为3T。由图5可以看出，实施例十二得到的稀土基纳米颗粒磁共振造影剂的纵向和横向弛豫率均高于临床常用造影剂。
图6是实施例十二得到的稀土基纳米颗粒磁共振造影剂在不同磁场强度下的弛豫率对比。由图6可以看出，实施例十二得到的稀土基纳米颗粒磁共振造影剂在高磁场强度和低磁场强度下均表现出较高的纵向和横向弛豫率。
本发明的稀土基纳米颗粒磁共振造影剂可以显著降低周围质子的弛豫时间，从而可以大幅提高局域组织的对比度。本发明申请所述的稀土基纳米颗粒磁共振造影剂具有弛豫率高、体内停留时间较长、注射剂量低、稀土离子游离可能性小等特点，可以有效提高诊断的准确性及造影剂的安全性。
虽然本发明以前述的实施例公开如上，然其并非用以限定本发明。本发明所属技术领域中的技术人员，在不脱离本发明的精神和范围内，当可做些许之更改与润饰。因此本发明的保护范围以权利要求书为准。

Claims (10)

1.一种稀土基纳米颗粒磁共振造影剂，其特征在于，其为包覆亲水性配体的稀土基无机纳米颗粒。
2.根据权利要求1所述的稀土基纳米颗粒磁共振造影剂，其特征在于，所述稀土基无机纳米颗粒的组成是MaREObXc，其中RE代表稀土元素，M代表碱金属或碱土金属，X代表氟或氯，0≤a≤1，0≤b≤1.5，0≤c≤4；或者所述稀土基无机纳米颗粒是以所述MaREObXc为基质进行掺杂的无机化合物。
3.根据权利要求1所述的稀土基纳米颗粒磁共振造影剂，其特征在于，所述稀土元素包括镧、铈、镨、钕、钐、铕、钆、铽、镝、钬、铒、铥、镱、镥、钪和钇中的一种或多种。
4.根据权利要求1所述的稀土基纳米颗粒磁共振造影剂，其特征在于，所述稀土基无机纳米颗粒的表面包覆配体是下列中的一种或多种：柠檬酸、半胱氨酸、聚乙烯醇、聚乙烯亚胺、聚乙烯吡咯烷酮、聚丙烯酸。
5.一种权利要求1所述稀土基纳米颗粒磁共振造影剂的制备方法，其特征在于，包括如下步骤：
1)在高沸点有机溶剂中，加入一定量的稀土前驱体或者稀土前驱体与非稀土前驱体的混合物，得到溶液A；
2)对溶液A抽真空以除去水分，然后在惰性气体保护下升温至250-340℃，维持15min-24h，然后冷却至室温，得到溶胶B；
3)对溶胶B进行离心分离，对所得沉淀物进行洗涤，再对沉淀物的表面进行亲水性配体的包覆；
4)将包覆后的颗粒分散于溶剂中，即得到造影剂。
6.根据权利要求5所述的方法，其特征在于：所述高沸点有机溶剂指油酸、亚油酸、油胺、十八烯、十六胺和十八胺中的一种或多种组成的混合溶剂。
7.根据权利要求5所述的方法，其特征在于：所述稀土前驱体是下列中的一种或多种的混合：稀土的氢氧化物、草酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、乙酰丙酮盐、苯基乙酰丙酮盐；所述非稀土前驱体是下列中的一种或多种的混合：碱金属与碱土金属的氟化物、氢氧化物、草酸盐、乙酸盐、三氟乙酸盐、三氯乙酸盐、乙酰丙酮盐、苯基乙酰丙酮盐。
8.根据权利要求5所述的方法，其特征在于：步骤1)中前驱体与溶剂的摩尔比是1:20-1:200；步骤2)在100-140℃下进行所述抽真空；步骤3)采用大量乙醇进行洗涤。
9.根据权利要求5所述的方法，其特征在于：步骤3)采用的洗涤方式为离心洗涤，洗涤次数为2-6次。
10.根据权利要求5所述的方法，其特征在于：步骤4)所述溶剂为水或生理盐水。
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