CN105188772A - 基于金属氧化物纳米颗粒的t1-t2双模式磁共振成像造影剂 - Google Patents
基于金属氧化物纳米颗粒的t1-t2双模式磁共振成像造影剂 Download PDFInfo
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- CN105188772A CN105188772A CN201380076498.3A CN201380076498A CN105188772A CN 105188772 A CN105188772 A CN 105188772A CN 201380076498 A CN201380076498 A CN 201380076498A CN 105188772 A CN105188772 A CN 105188772A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
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Abstract
本发明涉及一种磁共振成像(MRI)造影剂,尤其是基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,以及一种用于生产所述MRI造影剂的方法,该MRI造影剂不仅可用作T1?MRI造影剂,而且还可用作T2?MRI造影剂。通过在具有高的组织分辨率的T1成像与具有检测到病变的高可行性的T2成像之间有利的对比效果,基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂可提供比单一MRI造影剂更精确而详尽的与疾病相关的信息。
Description
技术领域
本发明涉及一种磁共振成像(MRI)造影剂,尤其是基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其不仅可用作T1MRI造影剂,而且可用作T2MRI造影剂。
背景技术
在各种分子成像技术中,磁共振成像(MRI)是功能最强大且非侵入式的诊断工具之一,因为MRI可在质子与组织周围分子的相互作用基础上提供具有极佳解剖细节的图像。
MRI造影剂是用于通过增加MRI中正常组织与异常组织之间的对比度来改善身体内部结构的可见度的一组造影剂。MRI造影剂改变组织和它们存在的体腔的T1(纵向的)和T2(横向的)弛豫时间。根据图像加权,这可以发出升高或下降的信号。大多数MRI造影剂通过缩短位于附近的质子的弛豫时间来起作用。
MRI造影剂是由自旋弛豫的两个主要的核磁共振过程:T1(纵向)、T2(横向)所定义(JournalofNuclearCardiology11(6):733-743,2004)。
用作T1MRI造影剂的顺磁金属离子主要加速T1弛豫并在T1加权图像中产生“明亮的”对比度,而用作T2MRI造影剂的超顺磁金属氧化物主要增加T2弛豫速率并产生“黑暗”对比效果。
T1-T2双模式MRI造影剂可提供比单一MRI造影剂更精确而详尽的与疾病相关的信息。MRI的T1-T2双模式策略引起了相当大的兴趣,因为它可通过具有高组织分辨率的T1成像和在检测病变方面具有高可行性的T2成像的有益的对比效果提供高精确度的诊断信息(Nat.Mater.5:971,2006)。迄今为止,还没有开发出适合于临床需求的T1-T2双模式MRI造影剂。由于用于医疗诊断的突出的优点,需要集中努力开发T1-T2双模式MRI造影剂。
在本说明书中已引用了许多论文和专利说明书,并在括号中标明了引用。所引用的论文和专利文件的说明随附于本发明中,以使本发明的技术和文本可更清楚地理解。
发明内容
技术问题
本发明的一个目的在于克服现有技术中的问题,并由此开发出需求已久的技术和方法。
准确地说,本发明的一个目的在于提供一种基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其不仅可用作T1MRI造影剂,而且还可用作T2MRI造影剂。
本发明的另一个目的在于提供一种用于生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,所述造影剂不仅可用作T1MRI造影剂,而且还可用作T2MRI造影剂。
技术方案
为提供基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,本发明人开发出一种方法从具有核(T1造影剂(contrastmaterial))-多孔壳(T2造影剂)结构的纳米颗粒通过以下步骤生成MRI造影剂:在惰性气体环境下合成T1造影剂的金属氧化物纳米颗粒,在惰性气体环境下在T1造影剂的金属氧化物纳米颗粒表面上形成T2造影剂的金属氧化物的外延层,在干燥空气环境下保持T2造影剂的金属氧化物层的形成以形成具有核和多孔壳结构的多层纳米颗粒,以及用生物相容聚合物涂覆多层纳米颗粒,随后通过证实所述基于纳米颗粒的MRI造影剂可用作T1-T2双模式MRI造影剂来完成本发明,所述T1-T2双模式MRI造影剂不仅可用作T1MRI造影剂,而且还可用作T2MRI造影剂。
所以,本发明提供一种从纳米颗粒得到的MRI造影剂,所述纳米颗粒具有核(T1造影剂)-多孔壳(T2造影剂)结构,以及用于生产所述MRI造影剂的方法。阐释本发明的一类示例性MRI造影剂的截面图如图1所示。
在本发明的一个优选实施方式中,选择氧化锰作为T1造影剂的金属氧化物,但不限于此,且还可选择其它金属氧化物,诸如氧化铬(III)和氧化钆(III)。更优选为氧化锰。本发明人先前已注意到氧化锰作为T1造影剂作用良好(Angew.Chem.Int.Ed.50:10589-10593,2011)。
在本发明的一个优选实施方式中,选择氧化铁作为形成多孔壳结构的金属氧化物,但不限于此,且还可选择其它超顺磁金属氧化物,这由氧化钴(II)和氧化镍(II)所例示,但不限于这些氧化物。更优选为氧化铁。
本发明的基于纳米颗粒的MRI造影剂的图像对比度增强由多层纳米颗粒的物理尺寸和形态决定(即高的表面积-体积比)。为了改善图像对比度增强,精密控制多层纳米颗粒的物理尺寸和形态至关重要。本发明可提供一种通过控制模板核(即T1造影剂的金属氧化物纳米颗粒)的物理尺寸和形态以控制多层纳米颗粒的这些特性的方法,从而提供高的表面积-体积比。可通过调节表面活性剂的量、反应时间和反应温度来控制模板核的这些因素。此外,本发明可选择任何形状的模板核,示例如下:八面体、十字形、海胆形以及立方纳米颗粒,但不限于这些。
可将各种聚合物用作以它涂覆多层纳米颗粒的生物相容聚合物。生物相容聚合物的优选例子包括生物聚合物,诸如壳聚糖、弹性蛋白、透明质酸、藻酸盐、明胶、胶原蛋白和纤维素;以及合成聚合物,诸如聚乙二醇(PEG)、聚氧化乙烯(PEO)、聚己酸内酯(PCL)、聚乳酸(PLA)、聚羟基乙酸(PGA),聚(乳酸-羟基乙酸)共聚物(PLGA)、聚(3-羟基丁酸酯-3-羟基戊酸酯)共聚物(PHBV)、聚对二氧环己酮(PDO),聚(L-丙交酯-己内酯)共聚物、聚(酯氨酯)(PEU)、聚(L-丙交酯-D-丙交酯)共聚物、聚(乙烯-乙烯醇)共聚物、聚(丙烯酸)(PAA)、聚(乙烯醇)(PVA)、聚乙烯吡咯烷酮(PVP)、聚苯乙烯(PS)和聚苯胺(PAN),但不限于这些。
所述生物相容聚合物可经修饰以改善MRI造影剂的生物相容性和稳定性。可用于聚合物修饰的方法已众所周知,并由所属领域的技术人员良好地执行,这意味着这些方法是非常普遍的,因此没有必要进一步解释。
所述生物相容聚合物可进一步经由与各种有用的部分(诸如靶标部分或诊断部分)结合得以修饰。所述靶标部分包括抗体、抗体片段、适配体以及与靶细胞表面上呈现的受体相结合的各种配体,但不限于此。并且所述诊断部分包括诊断成像部分,诸如荧光团、光学报道分子(reporter)和量子点;计算机断层扫描(CT)探针,诸如碘基化合物和金纳米颗粒;以及非金属放射性同位素,诸如铟(In)、锝(Tc)和氟(F),但不限于此。聚合物和有用部分的结合的方法已众所周知,并由所属领域的技术人员良好地执行,这意味着这些方法是非常普遍的,因此没有必要进一步解释。
本发明的MRI造影剂可通过将MRI造影剂颗粒分散在医药学上可接受的液体介质中制备。用于制备医药学上可接受的MRI造影剂可注射组合物的方法已众所周知,并由所属领域的技术人员良好地执行,这意味着这些方法是非常普遍的,因此没有必要进一步解释。
本发明还提供一种用于生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,所述造影剂具有T1造影剂的核和在所述核上形成的T2造影剂的多孔壳,所述方法包括以下步骤:
A)在惰性气体环境下合成T1造影剂的金属氧化物纳米颗粒;
B)在惰性气体环境下在T1造影剂的金属氧化物纳米颗粒表面上形成T2造影剂的金属氧化物的外延层;
C)在干燥空气环境下保持T2造影剂的金属氧化物层的形成以形成具有核和多孔壳结构的多层纳米颗粒;以及
D)用生物相容聚合物涂覆多层纳米颗粒。
在本发明的一个优选实施方式中,利用金属前驱物的热分解来合成T1和T2造影剂的金属氧化物,但不限于此方法,还可使用其它方法,诸如沉淀、气体蒸发法、混合气体法、喷雾干燥和机械合金法。
可利用多种金属盐作为金属前驱物,示例如下:金属乙酸盐、金属乙酰丙酮化物、金属溴化物、金属碳酸盐、金属氯化物、金属氟化物、金属碘化物、金属硝酸盐、金属硫酸盐、金属油酸盐、金属甲酸盐、它们的水合物形式,以及所述金属盐的混合物,但不限于这些。
作为用于金属前驱物热分解的表面活性剂,可使用烷基羧酸类,诸如油酸、月桂酸、硬脂酸、肉豆蔻酸(mystericacid)和棕榈酸;烷基胺类,诸如油胺、月桂胺、十六烷基胺、三辛胺和二辛胺;以及烷基羧酸类或烷基胺类的混合物,但不限于这些。作为烷基胺类,更优选初级烷基胺类,诸如油胺、月桂胺、十六烷基胺。
作为用于金属前驱物热分解的有机溶剂,优选具有比热分解反应的温度更高沸点的有机溶剂。例如碳氢化合物,诸如烷烃、烯烃、炔烃、环烷烃和二烯烃;醚化合物,诸如丁基醚、己基醚、辛基醚和癸基醚;杂环化合物,诸如吡啶和四氢呋喃;芳香族化合物,诸如甲苯、二甲苯、均三甲苯和苯;以及胺化合物,诸如三辛胺和油胺,但不限于这些化合物。
在干燥空气环境下在T1造影剂的金属氧化物纳米颗粒的表面上形成一层T2造影剂的金属氧化物的过程中,T1造影剂的金属氧化物纳米颗粒暴露于空气中形成较高氧化态的金属氧化物的薄层。例如,在氧的存在下,MnO纳米颗粒的表面部分地转化成Mn3O4相。这种氧化是不均匀的,导致在T1造影剂的金属氧化物纳米颗粒的表面上形成多个区域的较高氧化态的金属氧化物。T1造影剂的金属氧化物纳米颗粒表面上的较高氧化态形式的T1造影剂金属氧化物的小块的存在对于产生T2造影剂的多孔金属氧化物壳是至关重要的。由于在T2造影剂的金属氧化物壳中存在孔,因此T1造影剂可以容易地起作用。此外,在T1造影剂的金属氧化物纳米颗粒表面上形成T2造影剂的金属氧化物的外延层期间,较高氧化态的金属氧化物内的金属离子向外扩散至新形成的T2造影剂的金属氧化物壳。较高氧化态形式的T1造影剂的金属氧化物容易地与新形成的T2造影剂的金属氧化物相混合以形成经T1金属掺杂的T2造影剂的金属氧化物相。结果,可合成具有T1造影剂的核和T2造影剂的经T1金属掺杂的金属氧化物的壳的纳米颗粒。在某些情况下,此现象可提供额外的优点,诸如在T1-加权成像或T2-加权成像中图像对比度增强的改善。
因此,在干燥空气条件下进行在T1造影剂的金属氧化物纳米颗粒表面上产生T2造影剂的金属氧化物层的反应非常重要。
有益效果
本发明可提供一种用于生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,所述MRI造影剂不仅可用作T1MRI造影剂,而且还可用作T2MRI造影剂。通过在具有高的组织分辨率的T1成像与具有检测到病变的高可行性的T2成像之间有利的对比效果,根据本发明制造的MRI造影剂可提供比单一MRI造影剂更精确而详尽的与疾病相关的信息。根据本发明的方法,能够控制纳米颗粒的核和壳的物理尺寸和形态;因此,可期待增加T1-加权成像和T2-加权成像的图像对比度增强。
附图说明
参考附图可以更好地理解本发明的优选实施方式的应用,其中:
图1是阐释本发明的一类例示性MRI造影剂的截面图。
图2是八面体氧化锰(II)(MnO)纳米颗粒的透射电子显微镜法(TEM)图像。(a)是低倍放大,且(b)是高倍放大。
图3是合成的八面体MnO纳米颗粒的X射线衍射(XRD)图案。
图4是十字形MnO纳米颗粒的TEM图像。
图5是海胆形状MnO纳米颗粒的TEM图像。
图6是立方MnO纳米颗粒的TEM图像。
图7是阐释本发明的纳米颗粒的合成方案的简图。(a)是MnO纳米颗粒和,且(b)是具有中心MnO相的氧化铁纳米颗粒。
图8是根据本发明从八面体MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的TEM图像。(a)是低倍放大,且(b)是高倍放大。
图9是根据本发明从八面体MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的XRD图案。
图10是根据本发明从八面体MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的电子能量损失谱(EELS)分析的结果,显示氧(白色)、铁(红色)和锰(绿色)的元素映射图像。
图11是根据本发明从十字形MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的TEM图像。
图12是根据本发明从海胆形MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的TEM图像。
图13是根据本发明从立方MnO纳米颗粒得到的具有中心MnO相的氧化铁纳米颗粒的TEM图像。
图14是利用本发明的MRI造影剂所获得的T2-加权的MR图像。
图15是利用本发明的MRI造影剂所获得的T1-加权的MR图像。
具体实施方式
正如上文所述,本发明提供一种基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,以及一种用于生产所述MRI造影剂的方法,该MRI造影剂不仅可用作T1MRI造影剂,而且还可用作T2MRI造影剂。
本发明的实际和目前优选的实施方式如以下例子所示说明。
然而,基于对本公开内容的考虑,本领域技术人员可在本发明的精神和范围内进行修饰和改进。
实例1:制备各种形状的氧化锰(II)纳米颗粒
<1-1>制备八面体氧化锰纳米颗粒
通过使用报道的方法(Chem.Mater.18:1821,2006)经一些修改来合成八面体氧化锰(II)纳米颗粒。简单地说,将甲酸锰(II)(Mn(HCOO)2,5mmol)、油酸(13mmol)和三辛胺(15mmol)混合于50ml圆底烧瓶中。在强氩气气流下,将混合物在磁力搅拌下于油浴中加热到120℃并保持在所述温度3小时。随后以30℃每分钟的加热速率将温度增加到330℃并使反应保持在所述温度直到出现绿色。通过使反应溶液冷却至室温,并用1-丙醇洗涤,随后进行离心分离(3min,3,500rpm)而获得绿色固体。再次用乙醇洗涤几次所收集的固体,随后在烘箱中干燥过夜。TEM和XRD分析的结果分别如图2和图3所示。
<1-2>制备十字形氧化锰纳米颗粒
将乙酸锰(II)(1.4mmol)、油胺(3.0mmol)、油酸(1.5mmol)和三辛胺(6.2ml)装入100ml舒伦克管(Schlenktube)中。在磁力搅拌和氩气气流下,将舒伦克管在油浴中以18℃每分钟的加热速率加热到270℃并保持在所述温度1小时。随后将油酸(2.4mmol)和三辛胺(1.24ml)注入到反应混合物中,接着在270℃温度下进一步加热1小时。通过使反应溶液冷却至室温,并用1-丙醇洗涤,随后进行离心分离(3min,3,500rpm)来获得绿色固体。再次用乙醇洗涤几次所收集的固体,随后在烘箱中干燥过夜。TEM分析结果如图4所示。
<1-3>制备海胆形状氧化锰纳米颗粒
将6.2ml三辛胺、1.4mmol乙酸锰(II)、3mmol油胺和1.5mmol油酸添加到100ml舒伦克管中。在氮气覆盖层(吹出的N2气流速为40cc/min)下于油浴中将舒伦克管以18℃/分钟的速率加热到270℃。在270℃下1小时后,大的MnO纳米颗粒的形成得以完成。随后使所形成的大的多晶MnO纳米颗粒经受面选择性蚀刻。特别地,为了影响各向异性蚀刻,将油酸(1.6mmol)和三辛胺(1.24ml)注入到反应混合物中,并将所得溶液在270℃下进一步加热1小时。使反应混合物冷却到室温,并添加过量乙醇至溶液中,得到棕色沉淀物。TEM分析结果如图5所示。
<1-4>制备立方氧化锰纳米颗粒
将乙酸锰(II)(0.4mmol)、油酸钠(0.4mmol)、油胺(3.0mmol)、油酸(1.5mmol)和三辛胺(6.2ml)装入100ml舒伦克管中。在磁力搅拌和氩气气流下,将舒伦克管在油浴中以18℃每分钟的加热速率加热到270℃并保持在所述温度1小时。随后将油酸(2.4mmol)和三辛胺(1.24ml)注入到反应混合物中,接着在270℃温度下进一步加热1小时。通过使反应溶液冷却至室温,并用1-丙醇洗涤,随后进行离心分离(3min,3,500rpm)来获得绿色固体。再用乙醇洗涤几次所收集的固体,随后在烘箱中干燥过夜。TEM分析结果如图6所示。
实例2:制备具有中心MnO相的氧化铁纳米颗粒
<2-1>使用八面体氧化锰纳米颗粒制备具有中心MnO核的氧化铁纳米
颗粒
将14.2mg八面体MnO纳米颗粒和0.375mmol乙酰丙酮化铁(III)添加至100ml舒伦克管中油酸(0.05mmol)、油胺(1mmol)和三辛胺(2ml)的溶液中。在氩气下将舒伦克管在油浴中在强烈搅拌下以10℃/分钟的加热速率加热到210℃,并保持在此温度20min。随后在干燥空气环境下(氧气百分比为20%)将反应混合物在310℃下加热30min。将黑色溶液冷却到室温。冷却至室温后,随着丙酮和正丙醇的添加,具有中心MnO相核的氧化铁纳米颗粒沉淀下来,并通过离心分离(3min,3,500rpm)收集。所获得的纳米颗粒在己烷和乙醇中洗涤几次。阐释具有中心MnO核的氧化铁纳米颗粒的合成方案的简图如图7所示。具有中心MnO核的氧化铁纳米颗粒的TEM和XRD分析结果分别显示于图8和图9中。具有中心MnO核的氧化铁纳米颗粒的电子能量损失谱(EELS)分析的结果显示于图10中。
所得的纳米颗粒可再分散于氯仿、己烷或甲苯中以便进一步使用。
<2-2>使用各种氧化锰纳米颗粒制备具有中心MnO核的氧化铁纳米颗
粒
为了检查本发明的适用性,可使用各种氧化锰纳米颗粒进行具有中心MnO核的氧化铁纳米颗粒的制备。在这些实验中,具有中心MnO核的氧化铁纳米颗粒是通过与上述使用八面体氧化锰纳米颗粒制备具有中心MnO核的氧化铁纳米颗粒一样的方法来制备,只是使用十字形、海胆形或立方MnO纳米颗粒代替了八面体氧化锰纳米颗粒。
具有中心MnO核的氧化铁纳米颗粒的TEM分析的结果显示于图11-13中。
所得的纳米颗粒可再分散于氯仿、己烷或甲苯中以便进一步使用。
实例3:制备芘基聚乙二醇(芘基PEG)
通过使杂官能化聚乙二醇(NH2-PEGCOOH,分子量:5,000Da)的氨基与1-芘丁酸正羟基琥珀酰亚胺酯(Py-NHS,分子量:385.41Da)的正羟基琥珀酰亚胺(NHS)基结合来合成芘基聚乙二醇(芘基PEG)。详细地说,将3mmol的Py-NHS和1mmol的NH2-PEG-COOH溶于15ml二甲基甲酰胺中,且随后在室温下将200μl三乙胺添加至反应混合物中。在室温氮气氛下反应48小时后,过滤所得产物并用过量乙醚洗涤。使沉淀物在真空下干燥并储存以便日后使用。
实例4:涂覆具有芘基聚乙二醇(芘基PEG)的氧化铁纳米颗粒
将具有中心MnO核的氧化铁纳米颗粒于1ml四氢呋喃(THF)中的溶液注入含有300mg芘基PEG的50ml磷酸盐缓冲液(pH9.8)中。将所得悬浮液在室温下搅拌过夜以使有机溶剂蒸发,且随后在20,000rpm下离心分离45min三次。在移除上清液之后,将涂覆有芘基PEG的氧化铁纳米颗粒的沉淀物再分散在10ml磷酸盐缓冲盐水(PBS;pH7.4)中。
实例5:制备结合有抗体的MRI造影剂
为了有效目标,使实例4中制备的MRI造影剂与抗体结合。详细地说,将10μmol的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)和10μmol的硫代正羟基琥珀酰亚胺(硫代NHS)作为交联剂添加至实例4中制备的5mlMRI造影剂溶液中。随后添加0.7mg(4.5nmol)的抗HER2/neu抗体(;HER,罗氏制药有限公司(RochePharmaceuticalLtd.))。使混合物保持在4℃。6小时后,通过离心分离(20,000rpm,45min)纯化与抗体结合的MRI造影剂(HER结合的MRI造影剂)。同样地,通过与上述制备HER结合的MRI造影剂所进行的方法相同的方法使不相关的人免疫球蛋白G(IgG)抗体(IRR)与MRI造影剂结合,只是使用IRR代替了HER。所制备的IRR结合的MRI造影剂用作没有靶分子的对照MRI造影剂。
实例6:T2-加权的MR成像
将0.5mlHER结合的MRI造影剂给予无毛鼠。然后使用具有微-47表面线圈的3T临床MRI仪器(菲利普医疗系统,荷兰)进行MR成像。在室温下使用以下测量法获得在3T下注射了HER结合的MRI造影剂的无毛鼠的T2-加权的MR图像:TR=4,000毫秒均匀回波间隔(evenechospace),获得物的数目=1,点分辨率为312×312μm,截面厚度为0.6mm,以及TE=60毫秒。结果显示在图14中。
图14中的结果证实本发明的MRI造影剂可用作有效的T2MRI造影剂。
实例7:T1-加权的MR成像
将0.5mlHER结合的MRI造影剂给予无毛鼠。然后使用具有两个椭圆元件的11×14cmSENSEflexM线圈的3T临床MRI仪器(菲利普医疗系统,荷兰)进行MR成像。在3T下注射了HER结合的MRI造影剂的无毛鼠的T1-加权的MR图像具有0.07毫秒的选定回波时间。结果显示在图15中。
图15中的结果证实本发明的MRI造影剂可用作有效的T1MRI造影剂。
熟悉此项技术者将会了解到,在上述说明书中公开的概念和具体实施方式,可很容易地被用来作为修改或设计其它实施例用于执行本发明的相同目标的基础。熟悉此项技术者还将会了解这种等同的实施方式不脱离所附权利要求书中所阐述的本发明的精神和范围。
Claims (24)
1.一种基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述造影剂不仅用作T1MRI造影剂,而且还用作T2MRI造影剂。
2.根据权利要求1所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述金属氧化物是超顺磁的金属氧化物。
3.根据权利要求2所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物是至少一种选自由氧化铁、氧化钴和氧化镍组成的组的金属氧化物。
4.根据权利要求2所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物形成为具有至少一种选自由八面体、十字形、海胆形和立方形组成的组的形状。
5.根据权利要求2所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物包含T1造影剂的掺杂的金属离子。
6.一种用于生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,所述造影剂具有T1造影剂的核和在所述核上形成的T2造影剂的多孔壳,所述方法包括以下步骤:
A)在惰性气体环境下合成T1造影剂的金属氧化物纳米颗粒;
B)在惰性气体环境下在T1造影剂的金属氧化物纳米颗粒表面上形成T2造影剂的金属氧化物的外延层;
C)在干燥空气环境下保持T2造影剂的所述金属氧化物层的形成以形成具有核和多孔壳结构的多层纳米颗粒;以及
D)用生物相容聚合物涂覆多层纳米颗粒。
7.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述T1造影剂的金属氧化物纳米颗粒是至少一种选自由氧化锰纳米颗粒、氧化铬纳米颗粒和氧化钆纳米颗粒组成的组的金属氧化物纳米颗粒。
8.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述T1造影剂的金属氧化物纳米颗粒被合成为具有至少一种选自由八面体、十字形、海胆形和立方形组成的组的形状。
9.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述T2造影剂的金属氧化物是超顺磁的金属氧化物。
10.根据权利要求9所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述超顺磁的金属氧化物是至少一种选自由氧化铁、氧化钴和氧化镍组成的组的金属氧化物。
11.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述T2造影剂的金属氧化物层包含所述T1造影剂的掺杂的金属离子。
12.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述多层纳米颗粒具有所述T1造影剂的核和所述T2造影剂的壳,所述纳米颗粒具有至少一种选自由八面体、十字形、海胆形和立方形组成的组的形状。
13.根据权利要求6所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述生物相容聚合物是至少一种选自由以下各物组成的组的生物相容聚合物:生物聚合物,诸如壳聚糖、弹性蛋白、透明质酸、藻酸盐、明胶、胶原蛋白和纤维素;以及合成聚合物,诸如聚乙二醇(PEG)、聚氧化乙烯(PEO)、聚己酸内酯(PCL)、聚乳酸(PLA)、聚羟基乙酸(PGA),聚(乳酸-羟基乙酸)共聚物(PLGA)、聚(3-羟基丁酸酯-3-羟基戊酸酯)共聚物(PHBV)、聚对二氧环己酮(PDO),聚(L-丙交酯-己内酯)共聚物、聚(酯氨酯)(PEU)、聚(L-丙交酯-D-丙交酯)共聚物、聚(乙烯-乙烯醇)共聚物、聚(丙烯酸)(PAA)、聚(乙烯醇)(PVA)、聚乙烯吡咯烷酮(PVP)、聚苯乙烯(PS)和聚苯胺(PAN)。
14.根据权利要求13所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述生物相容的聚合物通过与靶标部分或诊断部分结合而修饰。
15.根据权利要求14所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述靶标部分选自由以下各物组成的组:抗体、抗体片段、适配体以及与靶细胞表面上显示的受体结合的各种配体。
16.根据权利要求14所述的生产基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂的方法,其特征在于,所述诊断部分选自由以下各物组成的组:诊断成像部分,诸如荧光团、光学报道分子和量子点;计算机断层扫描(CT)探针,诸如碘基化合物和金纳米颗粒;以及非金属放射性同位素,诸如铟(In)、锝(Tc)和氟(F)。
17.一种基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,所述造影剂通过根据权利要求6所述的方法制备。
18.根据权利要求17所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,所述纳米颗粒具有T1造影剂的金属氧化物的核和T2造影剂的金属氧化物的多孔壳。
19.根据权利要求18所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述T1造影剂的金属氧化物是至少一种选自由氧化锰、氧化铬和氧化钆组成的组的金属氧化物。
20.根据权利要求18所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述T2造影剂的金属氧化物是超顺磁的金属氧化物。
21.根据权利要求20所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物是至少一种选自由氧化铁、氧化钴和氧化镍组成的组的金属氧化物。
22.根据权利要求21所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物形成为具有至少一种选自由八面体、十字形、海胆形和立方形组成的组的形状。
23.根据权利要求20所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述超顺磁的金属氧化物包含所述T1造影剂的掺杂的金属离子。
24.根据权利要求23所述的基于金属氧化物纳米颗粒的T1-T2双模式MRI造影剂,其特征在于,所述T1造影剂的掺杂的金属离子是至少一种选自由锰离子、铬离子和钆离子组成的组的金属离子。
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