CN101340900A - 在磁共振成像中用作造影剂的纳米粒子 - Google Patents
在磁共振成像中用作造影剂的纳米粒子 Download PDFInfo
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- CN101340900A CN101340900A CNA2006800413116A CN200680041311A CN101340900A CN 101340900 A CN101340900 A CN 101340900A CN A2006800413116 A CNA2006800413116 A CN A2006800413116A CN 200680041311 A CN200680041311 A CN 200680041311A CN 101340900 A CN101340900 A CN 101340900A
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- gadolinium
- metal ion
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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Abstract
本发明涉及磁共振成像中用作造影剂的纳米粒子。所述纳米粒子由以下组成:具有惰性基质的核;一种或数种共价键合的有机配合剂,其中键合有一种或多种具有未成对电子的金属离子;及一种或多种任选的共价键合于所述核表面的生物分子。本发明还公开了制备所述纳米粒子的方法。
Description
本发明涉及纳米粒子(nanoscale particle)及其制备方法,所述纳米粒子由以下组成:具有惰性基质的核;一种或多种共价键合的有机配合剂,其中键合有一种或多种具有未成对电子的金属离子;及任选的一种或多种共价键合于所述核表面的生物分子。
由于其最优的信号转导作用(因7个未成对电子而具有强顺磁性,T1缩短),故钆(Gd)被用于MRI(磁共振成像)。由于7个未成对电子对,钆可诱导强电磁交变场,其影响相邻水质子自旋的方式使得它们的驰豫时间缩短。
静脉内施用钆盐溶液具有急性毒性作用。该毒性作用尤其影响平滑肌和横纹肌、线粒体功能及凝血。因此,已经尝试去寻找降低这种金属的毒性而不损害其顺磁性能即迁至磁场的趋势的方法。达到这个目标的最佳方法是螯合,其已导致含钆造影剂的工业化生产。
为此,使用配合物形成常数非常高的配合剂。这些配合剂的实例为DOTA和DTPA。
1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸 二亚乙基三胺五乙酸
迄今最稳定的市售钆螯合配合物是大环钆特酸(gadotericacid)(Gd-DOTA;市售可得,例如Guerbet的)。使用钆特酸作为MRI造影剂时,解离且由此释放毒性钆离子(LD50约0.1mmol kg-1)的风险非常低。与在酸性胃液中释放半衰期稳定性(在标准化模型0.1摩尔HCl溶液中测定)的范围从几秒至几小时的其他配合物相比,本文的钆特酸的半衰期超过一个月。钆与内源性金属离子如铜或锌的交换也显著低于1%,而在其他配合物中可高达35%。
钆完全被有机酸DOTA包围,且位于螯合分子的中心,如同在洞穴中,如X-射线晶体研究所示。因此,钆的毒性几乎被完全掩盖,而使它可用作MRI造影剂的顺磁性能得以保留。
MRI中造影剂的使用能增加器官显示的信息价值。正常情况下,静脉内注射10至15ml(0.2ml/Kg体重)的造影剂。所用含钆造影剂导致驰豫时间缩短,由此导致所生成影像中的信号增强。
基于过渡元素锰、铁或铜的造影剂仅用于特定问题的情形,特别是涉及到肝的情形。
顺磁性配合物如钆特酸具有亲水性,故不能通过血脑屏障。其静脉内注射后,发生迅速血管分布,继而间质分布;未观察到对于某种器官的优选性。所述配合物在几小时内借助肾小球过滤以原形经由肾脏***。钆特酸在3小时后被清除75%。所述药代动力学使Gd成为造影剂,其尤其适用于诊断发生在肿瘤、水肿、坏死和缺血情况下的细胞外液的运动。
Gd-DOTA的耐受性非常好。因此,两项超过5000例患者的研究已经显示:副作用发生率在0.84%-0.97%之间。两项研究中较大型的那项研究(Caillé1991)中,4169例患者只有8例出现恶心,5例出现呕吐,这些副作用的总发生率为0.31%。在所有患者的不到0.15%中,出现发热、头痛、不适感、皮疹及口腔气味不良。就钆特酸而言,***性渗透作用也可忽略。Gd-DOTA浓度明显增加的唯一器官是肾脏,这可能归因于药代动力学。然而,对肌酐清除率少于60ml/min的肾功能不全患者的耐受性研究显示:Gd-DOTA对重要参数或肾功能绝对没有副作用。与Gd-DOTA-BMA相比较,Gd-DOTA没有引起假低钙血症。对肾功能不全患者的建议:监测+采取所有措施预防肾功能不全(水化、剂量限制、风险/利益评估)。由于所有这些原因,钆特酸被批准作为MRI造影剂不仅用于成年人,而且用于儿童和婴儿。
含钆(III)的纳米粒子为公众所知已有几年,其较单独配合的钆(III)离子具有优势,这在作为诊断造影剂的应用中非常重要:
-与单独钆配合物相比,多个配合的钆(III)离子堆积在球表面,在磁共振成像中产生显著更强的信号。这使得能够降低造影剂的剂量,或者通过提高信噪比以相同剂量获得更强的信号。
C.Platas-lglesias等人,Chem.Eur.J.2002,8,No.22,5121-5131“具有很高驰豫性的沸石GdNaY纳米粒子用作磁共振成像造影剂”公开了加载Gd3+的沸石NaY纳米粒子,其中钆仅通过库仑力键合,即非共价键合。由于该Y沸石的孔径只有1.3nm,强烈地阻碍了自由质子与周围组织的交换。
WO 00/30688(Bracco)描述了取代的聚羧酸类配体分子和相应的金属配合物,如Gd-DTPA和Gd-DOTA衍生物,用作MRI的造影剂。
WO 2004/009134(Bracco)描述了作为MRI造影剂的钆螯合配合物,其被细胞所包围。
WO 96/09840(Nycomed)描述了包含粒状材料的诊断剂,其粒子包含具有诊断活性、基本上水不溶性的金属氧化物(氧化铁)的结晶材料,和聚离子性包衣剂(如壳聚糖、透明质酸、软骨素)。
WO 04/083902(Georgia Tech Research Corp.)描述了磁性纳米粒子(如钆螯合物),其具有生物相容性包衣(如磷脂-聚乙二醇),可携带生物分子如核酸、抗体等。
WO 03/082105(Barnes Jewish Hospital)描述了Gd-DTPA-PE和Gd-GTPA-BOA螯合配合物,其被脂质/表面活性剂包衣所包围。
本发明的目的是制备能避免上述化合物缺点的新型造影剂。
令人惊讶的是,通过使用高纯度二氧化硅作为共价键合的镧系配合物(优选钆配合物)的载体,已经实现上述目的。二氧化硅在患者体内具有极其良好的耐受性,因此远远优于其他很多现有技术中的材料。这方面的实例尤其参见以下文献:Jain,T.K.;Roy,I.;Dee,T.K.;Maitra,A.N.,J.Am.Chem.Soc.1998,120,11092-11095、Shimada,M.;Shoji,N,;Takahashi,A.,Anticancer Res.1995,15,109-115和Lal,M.;Levy,L.;Kim,K.S.;He,G.S.Wang,X.;Min,Y.H.;Pakatchi,S.;Prasad,P.N.,Chem.Mater.2000,12,2632-2639。
因此,本发明涉及纳米粒子,其由以下组成:具有惰性基质的核;一种或多种共价键合的有机配合剂,其中键合有具有未成对电子的金属离子;及任选的一种或多种共价键合于所述核表面的生物分子。
此外,本发明涉及纳米粒子,其由以下组成:具有惰性基质的核;任选的一种或多种共价键合于所述核表面的生物分子;及一种或多种有机配合剂,其经由连接体共价键合于所述核表面,且其中键合有具有未成对电子的金属离子。
具有惰性基质的核或载体优选由二氧化硅、二氧化钛、氧化铝或二氧化锆组成。特别优选二氧化硅。单分散二氧化硅粒子通过已知方法(参见EP 0216278)、经水解四烷氧硅烷而制备。此处单分散粒子的平均粒径为10至500nm、优选30至300nm。然而,原则上,也可使用聚合物如聚苯乙烯晶格(lattices)。
此外,在第一步骤中可能用二氧化硅薄层包衣其他纳米粒子。可能通过本领域技术人员已知的溶胶-凝胶方法、以简单的方式进行包衣。为此,将纳米粒子悬浮于乙醇/水溶液中,加入硅酸酯如原硅酸四乙酯(TEOS)。硅酸酯的水解通过加入氨水溶液启动,如果必要,在升高的温度进行。沉淀的二氧化硅优选沉积在悬浮液中的纳米粒子上。根据待包衣纳米粒子的已知量和已知平均直径,通过所用硅酸酯的量可非常精确地调整层的厚度。
通过以粒子直径>约50nm超滤或离心,可分离或纯化经包衣的纳米粒子。
所用金属离子优选镧系元素的顺磁性离子。特别优选使用钆(III)离子。
所用有机配合剂优选为低聚羧酸或聚羧酸(polycarboxylate)类化合物。特别优选使用二亚乙基三胺五乙酸(DTPA)或1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)。
金属螯合配合物经由连接体、优选经由硅烷共价键合于载体表面。优选的连接体为3-氨基-丙基三乙氧基硅烷(APTES)。
经由铜催化的叠氮化物(azidene)和炔烃的偶极1,3-环加成反应即所谓的Huisgen反应制备金属螯合配合物是特别有利的。本领域技术人员已知的这种反应在非常温和的条件下、以优异产率生成稳定的1,2,3-***,并以简单的方式使非常复杂分子的合成变得容易。因此,最近该反应以术语“点击化学(Click chemistry)”已经再次吸引人们越来越多的兴趣,这反映在大量的出版物中(参见等人,Angew.Chem.2005,117,5336;Kolb,Finn和Sharpless,Click Chemistry:Diverse Chemical Function from a FewGood Reactions,Angew.Chem.Int.Ed.2001,40,2004-2021)。
令人惊讶的是,已经发现:上述Huisgen反应也可有利地用于纳米粒子表面的功能化。这意味着“点击化学”也可用于纳米粒子上的非均相固相反应。
因此,本发明进一步涉及制备纳米粒子的方法,该方法包括以下方法步骤:
a)通过湿法化学(wet-chemical)方法制备纳米粒子,优选由二氧化硅、二氧化钛、氧化铝和/或二氧化锆制备,
b)用卤代硅烷的单分子层包衣所述纳米粒子,
c)使所述纳米粒子与含叠氮基团的试剂反应,得到被叠氮基团功能化的纳米粒子,
d)制备一种或多种有机配合剂,其含有一种或多种胺和一种或多种聚羧酸、聚羧酸酐、聚碳酰氯或聚羧酸酯,
e)用来自镧系的金属离子加载一种或多种配合剂,
f)使步骤c)的经叠氮基团功能化的纳米粒子与步骤e)的加载有金属离子的有机配合剂反应。
所用卤代硅烷优选例如3-氯丙基-三乙氧基硅烷。
所用炔胺可以是所有已知的炔胺,优选使用炔丙胺或6-氨基-1-己炔。使其与适合于配合物形成的聚羧酸、聚羧酸酐、聚碳酰氯或含有良好离去基团的聚羧酸酯反应。甲酰胺由已知的方法合成。
作为聚羧酸,使DOTA和DTPA或其衍生物(例如Li盐)优选与相应的胺反应。应确保在反应期间,聚羧酸的仅一个羧酸功能团与胺反应(1∶1批)。例如,DTPA二酐与炔丙胺的反应通过已知的Schotten-Baumann方法进行。
生物分子如酶、肽/蛋白质、受体配体或抗体,可另外共价键合于纳米粒子。其特异性偶联于患者体内的靶组织使成像和随后的诊断简单化。
纳米粒子可进一步用葡聚糖或聚乙二醇包衣以提高生物相容性。
本发明进一步涉及纳米粒子作为磁共振成像造影剂的用途。根据本发明的粒子可用作磁共振成像的造影剂,因为排列在表面上的金属离子能够与周围的质子如组织液的质子相互作用。
以下实施例用来更详细地解释而非本发明。
实施例1
表面键合有Gd(III)、平均粒径为250nm的单分散二氧化硅粒子的制备
1.1制备单分散二氧化硅粒子
如EP 0216278 B1所述、通过在水/乙醇/氨介质中水解四烷氧基硅烷制备单分散二氧化硅粒子,其中首先制备原始粒子的溶胶,随后通过连续计量加入四烷氧基硅烷以控制反应程度,使所得SiO2粒子达到所需粒子大小。
1.2用3-氨基丙基三乙氧基硅烷(APTES)功能化
将在第一步骤中制得的10g二氧化硅粒子悬浮于20ml 2-丙醇中。随后滴加用5ml 2-丙醇稀释的0.25ml APTES,将混合物用回流冷凝器在80℃搅拌2小时。
借助离心机以4000min-1将悬浮液用2-丙醇洗涤8次,直至借助茚三酮的点滴试验在洗液中检测不到APTES。
1.3用二亚乙基三胺五乙酸(DTPA)形成酰胺
将25ml二甲基亚砜(DMSO)加至在第二步骤中用APTES功能化的二氧化硅粒子,将2-丙醇在旋转蒸发仪中真空蒸出。随后将0.58g二亚乙基三胺五乙酸二酐(DTPA-ca)加至该悬浮液中,将混合物在150℃搅拌2小时。冷却至室温后,将反应产物倾至200ml 0.1N TRIS缓冲液(pH7.0),用去离子水在离心机中洗涤多次。
1.4加载钆(III)离子
将0.486g无水氯化钆(III)加至在第三步骤中得到的悬浮液,将混合物在室温搅拌8小时。随后利用离心机、用去离子水洗涤该悬浮液,直至借助硝酸银溶液在水洗液中检测不到氯化物。然后将反应产物冷冻干燥。
表征:
将经干燥的加载钆的二氧化硅粒子溶解于稀氢氟酸中,通过ICP-MS检测钆含量。在样品中发现0.13%的钆。
将二氧化硅粒子样品再次用去离子水充分洗涤(3×),干燥后,通过ICP-MS重新分析。检测到钆含量为0.14%。略微较高的钆含量可以解释为:干燥的程度不同或检测方法的局限性。然而,关键的因素是重复洗涤二氧化硅粒子并没有减少钆的含量,即显然钆非常坚固地共价键合于无孔二氧化硅粒子的表面。用1N盐酸处理的情况下也获得了相同的结果。
实施例2
表面键合有Gd(III)、平均粒径为90nm的单分散二氧化硅粒子的制备
1.1粒子的制备
如EP 0216278 B1的实施例4所述。
1.2粒子的功能化
将在第一步骤中制得的10g二氧化硅粒子悬浮于20ml 2-丙醇中。随后滴加用5ml 2-丙醇稀释的0.50ml APTES,将混合物用回流冷凝器在80℃搅拌2小时。
借助离心机以4000min-1将悬浮液用2-丙醇洗涤8次,直至借助茚三酮的点滴试验在洗液中检测不到APTES。
1.3用二亚乙基三胺五乙酸(DTPA)形成酰胺
将25ml二甲基亚砜(DMSO)加至在第二步骤中用APTES功能化的二氧化硅粒子,将2-丙醇在旋转蒸发仪中真空蒸出。随后将1.0g二亚乙基三胺五乙酸二酐(DTPA-ca)加至该悬浮液中,将混合物在150℃搅拌2小时。冷却至室温后,将反应产物倾至200ml 0.1N TRIS缓冲液(pH7.0),用去离子水在离心机中洗涤多次。
1.4加载钆(III)离子
将1.0g无水氯化钆(III)加至在第三步骤中得到的悬浮液,将混合物在室温搅拌8小时。随后利用离心机、用去离子水洗涤该悬浮液,直至借助硝酸银溶液在水洗液中检测不到氯化物。然后将反应产物冷冻干燥。
表征:
将经干燥的加载钆的二氧化硅粒子溶解于稀氢氟酸中,通过ICP-MS检测钆含量。
在样品中发现0.2%的钆。与实施例1制备的粒子相比较,较高的钆含量可以解释为:较小的粒子具有较高的表面积/容积比。经计算,约1200个钆离子加载于一个90nm粒子的表面。
实施例3
表面键合有Gd(III)、平均粒径为250nm的单分散二氧化硅粒子的制备
3.1制备二氧化硅纳米粒子
在室温将16.7ml原硅酸四乙酯加至41.5ml软化水与111ml乙醇的混合物中,通过搅拌制备均相溶液。随后加入26ml 25%重量的氨溶液,将混合物再剧烈搅拌15秒,然后静置1小时。加入氨溶液后约1分钟,从溶液的混浊可观察到连续缩合得到二氧化硅纳米粒子。该反应混合物不经处理,而是直接用于下一反应步骤。
3.2与卤代硅烷反应
将在第一步骤中制得的纳米粒子用卤代硅烷的单分子层包衣。为此,将80μl 3-氯丙基-四乙氧基硅烷加至第一步骤的反应混合物中,将该混合物在80℃搅拌5小时。随后离心出粒子,用软化水洗涤直至中性。
3.3制备表面键合的叠氮化物
将在第二步骤中制得且经洗涤的纳米粒子悬浮于50ml软化水中,加入66mg叠氮化钠,将该混合物在50℃搅拌24小时。卤素氯通过亲核取代被拟卤素叠氮基所替代。在离心机中从起始材料分离含叠氮基的纳米粒子,用软化水洗涤,以水性悬浮液保存。
3.4通过DTPA二酐与炔丙胺的反应(Schotten Baumann方法)制备炔 烃(聚羧酸单炔酰胺)
将0.19g(1mmol)1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(EDC)(Aldrich)、0.15g(1.5mmol)三乙胺(Merck)和2ml二甲基甲酰胺(Merck)加至0.62g(1mmol)二亚乙基三胺-1,7-四(乙酸叔丁基酯)-4-乙酸(Macrocyclics公司的Article B-365)。在室温剧烈搅拌10分钟后,加入0.06g(1mmol)炔丙胺。
将该反应混合物在室温再搅拌8小时。通过薄层色谱法监测反应。将反应混合物加至10ml二氯甲烷中,用20ml 0.1摩尔盐酸振摇洗涤3次,再用20ml饱和NaHCO3水溶液洗涤3次。最后将混合物用饱和氯化钠水溶液振摇洗涤,用无水硫酸钠干燥。在旋转蒸发仪中蒸出二氯甲烷,将油状残渣加至4ml四氢呋喃/乙醇(容积比1∶1)中。将1ml水和0.1g(4.4mmol)氢氧化锂加至该混合物中,以裂除酯保护基团。将水解混合物搅拌过夜,在旋转蒸发仪中蒸发至干。将反应产物加至10ml水中,用1摩尔盐酸调整pH至7。
3.5用钆(III)离子加载配合剂
将10ml 0.1摩尔氯化钆(III)溶液(=1mmol)加至第四步骤制得的二亚乙基三胺五乙酸4-炔丙酰胺的锂盐溶液中,将混合物搅拌30分钟。
3.6制备用配合剂分子修饰的纳米粒子(Huisgen反应)
借助TRIS缓冲液将第三步骤制得的、用叠氮基功能化的纳米粒子悬浮液调整至中性pH。将预先计算量的聚羧酸单炔酰胺(由第五步骤)滴加至含有50mg氯化铜(I)的纳米粒子悬浮液中。在室温搅拌16小时后,将反应终止。离心出粒子,用0.1摩尔盐酸剧烈洗涤3次,最后用软化水洗涤。
借助ICP-MS检测粒子的钆含量为0.3%。
Claims (17)
1、纳米粒子,其由以下组成:
-具有惰性基质的核,
-一种或多种共价键合的有机配合剂,其中键合有一种或多种具有未成对电子的金属离子,和
-任选的一种或多种共价键合于所述核表面的生物分子。
2、纳米粒子,其由以下组成:
-具有惰性基质的核,
-任选的一种或多种共价键合于所述核表面的生物分子,和
-一种或多种有机配合剂,其经由连接体共价键合于所述核表面,且其中键合有具有未成对电子的金属离子。
3、根据权利要求1和/或2的纳米粒子,其特征在于:所述核由二氧化硅、二氧化钛、氧化铝和/或二氧化锆组成。
4、根据权利要求3的纳米粒子,其特征在于:所述核由二氧化硅组成。
5、根据权利要求1至4的一项或多项的纳米粒子,其特征在于:它们平均粒径为10-500nm、优选30-300nm且为单分散粒子。
6、根据权利要求1至5的一项或多项的纳米粒子,其特征在于:所述金属离子选自镧系元素。
7、根据权利要求1至6的一项或多项的纳米粒子,其特征在于:所述金属离子为钆(III)离子。
8、根据权利要求1至7的一项或多项的纳米粒子,其特征在于:所述有机配合剂选自低聚羧酸或聚羧酸类。
9、根据权利要求8的纳米粒子,其特征在于:所述有机配合剂为二亚乙基三胺五乙酸(DTPA)或1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)。
10、根据权利要求1至9的一项或多项的纳米粒子,其特征在于:所用共价键合的生物分子为酶、肽/蛋白质、受体配体或抗体。
11、根据权利要求2的纳米粒子,其特征在于:所用连接体为硅烷。
12、根据权利要求11的纳米粒子,其特征在于:所用连接体为3-氨基丙基三乙氧基硅烷(APTES)。
13、制备纳米粒子的方法,其包括以下方法步骤:
a)通过湿法化学方法制备纳米粒子,优选由二氧化硅、二氧化钛、氧化铝和/或二氧化锆制备,
b)用卤代硅烷的单分子层包衣所述纳米粒子,
c)使所述纳米粒子与含叠氮基团的试剂反应,以获得用叠氮基团功能化的纳米粒子,
d)制备一种或多种有机配合剂,其含有一种或多种胺和一种或多种聚羧酸、聚羧酸酐、聚碳酰氯或聚羧酸酯,
e)用来自镧系的金属离子加载一种或多种配合剂,
f)使步骤c)的用叠氮基团功能化的纳米粒子与步骤e)的加载有金属离子的一种或多种有机配合剂反应。
14、根据权利要求13的方法,其特征在于:在步骤d)中由有机配合剂如1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)或二亚乙基三胺五乙酸(DTPA)或其衍生物和相应的炔胺制备聚羧酸单炔酰胺。
15、根据权利要求13和/或14的方法,其特征在于:步骤d)中所用的炔胺为炔丙胺或6-氨基-1-己炔。
16、根据权利要求13至15的一项或多项的方法,其特征在于:步骤e)中所用的金属离子为钆(III)离子。
17、根据权利要求1至12的一项或多项的纳米粒子作为磁共振成像造影剂的用途。
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