CN101365496A - 用于磁共振成像的靶向性纳米粒子 - Google Patents
用于磁共振成像的靶向性纳米粒子 Download PDFInfo
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Abstract
在一些实施方式中,本发明涉及用于磁共振成像(MRI)的新型靶向性造影剂。本发明也涉及制备该靶向性MRI造影剂的方法和使用该MRI造影剂的方法。通常,这种靶向性MRI造影剂提供增强的弛豫率、改善的信噪比、靶向性和抗凝聚性。制备这种MRI造影剂的方法通常提供更好的控制粒度,并且使用这种MRI造影剂的方法通常提供提高的血清除率和生物分布。
Description
技术领域
[0001]本发明整体涉及一种用于诊断成像的纳米粒子,更具体地讲,本发明涉及一种在磁共振成像中用作造影剂的靶向部分(moiety)官能化的纳米粒子。
背景资料
[0002]诊断成像处理和造影剂被用于研究身体的器官、组织和疾病。成像技术的一个例子包括磁共振(MR),所述磁共振是一种使用强磁场和无线电信号以形成身体内部结构和器官的复杂的垂直横截面和三维图象的技术。与使用了潜在有害的射线(X射线)的传统的X射线和计算机断层(CT)成像不同,磁共振成像(MRI)基于原子的磁性。MRI在提供含有水的组织和器官例如脑、内脏、腺体、血管和关节的图象方面是最有效的。当聚集的无线电脉冲沿着所关注的组织中按磁场方向排列的氢原子传播时,该氢原子返回作为质子弛豫结果的信号。来自不同身体组织的信号的细微差别能够使MRI区别器官,并且潜在地对比良性和恶性组织。MRI对于检测肿瘤、出血、动脉瘤、病变、病变堵塞、感染、关节损伤等方面是有用的。
[0003]造影剂改变了其分布(occupy)的组织的驰豫时间。用于MRI的造影剂为典型的磁性材料,由于造影剂的磁矩和水质子之间与时间相关的磁偶极相互作用,该磁性材料提高了近距离内水质子的弛豫时间。质子的弛豫时间被缩短的效率定义为弛豫率(R1=1/T1,R2=1/T2)。MRI造影剂可为使其分布的组织增亮的阳性造影剂(T1剂),或为使组织看起来更暗的阴性造影剂(T2剂)。对于体内诊断,MRI提供了优良的分辨特性(约2mm),然而,当与其他成像技术相比时,其提供了较差的灵敏度。造影剂的施用极大改善了成像灵敏度。顺磁性钆(Gd)物质(T1剂)例如Gd-DTPA(例如已在临床上用作MRI造影剂。
[0004]超顺磁性氧化铁纳米粒子(SPIO)在医学上已经被评定为MRI造影剂。这些产品中的一些可购自市场,例如作为造影剂的Feridex和其用于肝脏和脾成像的临床应用。超顺磁性造影剂受磁化程度高于顺磁性造影剂,因为其磁矩比顺磁性造影剂高约1000倍,所述磁矩可提供更高的驰豫率(Andre E.Merbach和Eva Toth(编),TheChemistry of Contrast Agents in Medicinal Magnetic Resonance Imaging,Wiley,New York,2001,p.38;ISBN 0471607789)。超顺磁性氧化铁晶体结构具有通式[Fe2 3+O3]x[Fe2 3+O3(M2+O)]1-x,其中1≥x≥0。M2+可为二价金属离子例如铁、锰、镍、钴、镁、铜或其组合。当所述金属离子(M2+)为亚铁离子(Fe2+)并且x=0时,SPIO造影剂为磁铁矿(Fe3O4),当x=1时,SPIO造影剂为磁赤铁矿(γ-Fe2O3)。当不成对自旋的晶体区域充分大以致于可将它们视为热力学独立的、可被称为磁畴的单畴粒子时,超顺磁性现象发生。这种磁畴的净磁偶极子大于其单独的不成对电子的总和。当外加磁场消失时,所有磁畴无规取向,没有净的磁化强度。外部磁场引起所有磁畴的偶极矩重新取向,导致了净磁矩。T1,T2和T2*弛豫过程被SPIO缩短。在室温下和在1.5特斯拉的磁场中,R2弛豫率的范围为40-60mM-1s-1,R1弛豫率的范围为10-20mM-1s-1。所述弛豫率基本上大于顺磁性造影剂例如Gd-DTPA的弛豫率,对于该顺磁性造影剂,R2为4mM-1s-1,R1为3mM-1s-1。SPIO的弛豫率取决于多种因素,例如粒度、组成、涂料化学、表面电荷和粒子稳定性。弛豫率的比率R2/R1一般用于量化由SPIO制造的造影的类型。在R2/R1值小于10时,SPIO的T1(阳性)效应可使用T1-加权序列而加强。在R2/R1值大于10时,T2效应占优势并且所述造影剂为T2/T2*剂。阳性造影技术最近已被用于显示用SPIO标记的细胞(Mag.Res.Medicine 2005:53:999-1005,C.H.Cunningham等人)。这样,SPIO造影剂在用作阳性或阴性造影剂上提供了巨大的灵活性。
[0005]造影剂特异性(specificity)为提高所关注位置的信噪比及通过成像提供功能信息所需的特性。造影剂的自然生物分布取决于其粒度、电荷、表面化学和施用途径。造影剂可集中在健康组织或病变位置并增加正常组织和病变组织之间的对比。为了增加对比,必需在所关注的位置集中造影剂并提高弛豫率。另外,,也期望相对于健康细胞可增加造影剂被病变细胞的摄入。
[0006]多数造影剂有些器官特异性,原因在于其被肝脏或肾排泄。因为显著降低的弛豫性,使用钆螯合物作为受体导向剂的最初研究需要高剂量的造影剂(Eur.Radiol.2001.11:2319-2331,Y.-X.J.Wang,S.M.Hussain,G.P.Krestin)。与钆螯合物相比,磁铁矿粒子拥有大到约2到3个数量级的磁化率(Eur.Radiol.2001.11:2319-2331,Y.-X.J.Wang,S.M.Hussain,G.P.Krestin)。因此,氧化铁造影剂潜在地在比钆螯合物更低的剂量下提供了更强的信号。由于在给定组织内可连接的标靶物的数量限制,氧化铁造影剂更高的灵敏度具有另外的好处。
[0007]有多种磁性纳米粒子例如磁性树状大分子、磁性脂质体和聚合物涂层的纳米粒子(例如葡聚糖、聚乙烯醇等),所述聚合物涂层的纳米粒子由嵌入有机涂层内的结晶的超顺磁性氧化铁纳米粒子构成。这些纳米粒子通常被评定用于磁分离、细胞跟踪和成像。一些目前正被进行临床应用测试,例如肝脏和脾成像、肠造影和MR血管造影。这些造影剂的水力直径(DH)通常在约20nm至约400nm的范围内,并且大部分造影剂由于被网状内皮系统(RES)的摄入快速地从血液清除。它们主要是用于组成RES系统的器官(特别是肝脏)的造影剂。为了成像其他器官,较小的粒度通常是必要的。
[0008]大部分的商业造影剂(DH=80-150nm)和那些在3阶段(phase)试验(DH=20-80nm)的造影剂是基于葡聚糖或葡聚糖衍生物的,其中使用了相对小的粒子。然而,葡聚糖涂层在粒子合成的碱性条件下已经被声称是不稳定的,因此它们的化学成分受到质疑。另外,葡聚糖诱导的过敏反应存在潜在的问题(R.Weissleder US 5,492,814)。
[0009]通常,氧化铁纳米粒子在水溶性有机分子例如葡聚糖的存在下,从碱性水溶液合成并沉淀,并且这种纳米粒子通常具有有机涂层。通过这种方法获得的纳米粒子趋向具有宽的超顺磁性氧化铁的粒度分布,并且,结果,涂层的粒子也显示了宽的粒度分布。另外,此方法对于涂覆程度控制较差,导致了粒子在单个造影剂中包含多种氧化铁纳米粒子。为了获得期望的粒度,包括多次的纯化和粒析步骤的广泛的制造技术是必要的。粒度以及有机涂层组合物非常重要,因为其直接影响纳米粒子的药物动力学。氧化铁的粒度与造影剂的超顺磁性和弛豫率直接相关。因此,宽的粒径分布通常转变成平均灵敏度。
[0010]使用传统方法获得的纳米粒子还具有低水平的结晶度,其显著影响造影剂的灵敏度。此外,由于纳米粒子的高的表面能,其趋于凝聚,这是在合成和纯化步骤期间遇到的重要的问题。这种凝聚增加了粒子的粒度,从而导致了快速的血液清除以及降低了靶向效率,并且可导致弛豫率的降低。粒度、血液循环时间和有机涂层以不同的方式影响靶向效率。当使用大的粒子时,仅仅少数靶向性配体可在粒子大到足以激活RES之前被粘附,从而导致其从血液几乎瞬间清除以及造影剂无法到达指定的标靶物。更小的粒度在生物标志物和配体间发生识别的位置可更有“粘性”。当涂层为球状时,用于配体粘附的活性位置通常被阻碍,从而降低了结合效率。另外,一旦结合,配体会停留在球状涂层的内部,阻碍了其对生物标志物的易于接触。
[0011]目前的成像剂和方法主要提供解剖学信息。然而,潜在的病情是在表面的身体症状出现前广泛传播疾病的生化过程。具有在疾病的早期阶段成像生化途径或在途径中的特异性标志(生物标志物或生理变化)的能力将提供功能信息。这可称为“靶向分子成像”。为了举例说明,在动脉硬化症的情况下,由于在斑块形成前很长时间的化学事件的级联(cascade),脂质条纹或病变得以形成。此外,通过增加血管壁的外直径,身体能够适应这种情况,使得任何积聚的斑块不被。一旦斑块达到临界尺寸,其才会被发现,并导致阻塞的血液流动,或当其破裂时,可导致血栓(血凝块)形成,从而导致急性心肌梗塞或死亡。
[0012]需要对能够探测增加的关键化学生物标志物的具体分子标记物标靶,并从而提供特异病情早期的生化信息的造影剂。需要能够标靶活动性炎症的位置并且响应病变的生理信号的分子造影剂以满足疾病的早期诊断和处理的医学需要。在分子成像和造影剂的靶向施用中,一个主要的发展需求是识别生物标志物。然而,造影剂的固有的问题限制了靶向效率,例如低灵敏度、低信噪比、大的粒度、快速的血液清除、低的配体粘附效率和配体到生物标志物的标靶的可达性。
[0013]上述造影剂靶向施用的例子包括使用涂覆有交联葡聚糖的氧化铁纳米粒子并随后添加抗体或肽((Kelly,K.A.,Allport,J.R.,Tsourkas,A.,Shinde-Patil,V.R.,Josephson,L.,and Weissleder,R.(2005)Circ Res 96,327-336;Wunderbaldinger,P.,Josephson,L.,and Weissleder,R.(2002)Bioconjug Chem 13,264-268)。当分子的偶联(conjugation)和向所关注的位置的造影剂施用完成时,所述造影剂通过生物结合变的非常大(>65nm)并且显示了可显著影响人的功效的非常低的血液半衰期(<50分钟)。另一个例子包括使用2,3-二巯基丁二酸(DMSA)离子官能化单分散性的9nm氧化铁芯,并且偶联马来酰亚胺-官能化的Her2-特异性抗体到DMSA-纳米粒子(Huh,Y.M.,Jun,Y.W.,Song,H.T.,Kim,S.,Choi,J.S.,Lee,J.H.,Yoon,S.,Kim,K.S.,Shin,J.S.,Suh,J.S.,andCheon,J.(2005)J Am Chem Soc 127,12387-12391;Jun,Y.W.,Huh,Y.M.,Choi,J.S.,Lee,J.H.,Song,H.T.,Kim,S.,Yoon,S.,Kim,K.S.,Shin,J.S.,Suh,J.S.,and Cheon,J.(2005)J Am Chem Soc 127,5732-5733)。所获得的非共价的生物结合的纳米粒子具有28nm的水合直径和已被证实了的对于体内癌细胞的靶向性。这项技术的主要局限性是测量的这些造影剂的Msat值对于4-6nm核纳米粒子在43-60emu/g之间。当这些粒子位于所关注的疾病位置时,这些相对低的Msat值会深刻的影响这些粒子的成像。另外,DMSA-纳米粒子的相互作用是离子作用而不是共价作用,其可降低在注入后靶向分子保持粘附于纳米粒子上的能力。概括地说,确定新策略将靶向分子共价粘附到具有小于10nm直径的核的强磁性(>60emu/g)的单分散性纳米粒子,将非常有价值。
[0014]极大需要改进探测的限制、提高分辨率、提供整体成像、获得分子级别的信息、在早期阶段发现疾病和通过MRI研究获得生理信息。这些挑战需要改善造影剂的灵敏度、选择性、血液循环时间以及生物标志物和靶向配体的表征。
[0015]作为前述的结果,一种方法和/或组合物将是非常有用的,通过该方法/使用该组合物,纳米粒子将具有提高的弛豫率、信噪比、具有抗凝聚的靶向性能和控制粒度、血清除率和生物分布的能力。
具体实施方式
[0016]在一些实施方式中,本发明涉及一种用于磁共振成像(MRI)的新型靶向性造影剂。本发明也涉及制备该靶向性MRI造影剂的方法和使用该MRI造影剂的方法。通常,该靶向性MRI造影剂提供增强的弛豫度、改善的信噪比、靶向性和抗凝聚性。制备该MRI造影剂的方法通常提供更好的粒度控制,并且使用这种MRI造影剂的方法通常提供提高的血清除率和生物分布。
[0017]在一些实施方式中,本发明涉及靶向性造影剂,其包含:(a)无机基磁芯;(b)有机基非磁性涂层,所述非磁性涂层分布在所述无机基磁芯周围并连接在该无机基磁芯上,从而在整体上,所述磁芯和所述非磁性涂层形成了核/壳纳米粒子;和(c)粘附在所述核/壳纳米粒子上的标靶物,从而在整体上,所述核/壳纳米粒子和所述标靶物形成了靶向性MRI造影剂。
[0018]在一些实施方式中,本发明涉及制造上述靶向性MRI造影剂的方法,该方法包含以下步骤:a)合成纳米粒子的核;b)合成纳米粒子的壳以使所述纳米粒子的核基本上被所述壳覆盖;和c)将标靶分子粘附到所述纳米粒子壳上。
[0019]在一些实施方式中,本发明涉及在成像技术例如MRI中使用上述靶向性造影剂的方法。这些使用可包括向体外细胞的施用和/或哺乳动物的体内受体的施用。
[0020]前面已相当广泛地概述了本发明的特征,从而使得可更好地理解以下本发明的详细说明。本发明的另外的特征和优点将在下文中进行描述,其组成了本发明权利要求的主题。
附图说明
[0021]为了更完整的理解本发明和其优点,现在结合附图参考以下说明,其中:
[0022]图1根据本发明的一些实施方式,描绘了用在靶向性MRI造影剂中的核/壳纳米粒子的理想化剖视图;
[0023]图2根据本发明的一些实施方式,描绘了靶向性MRI造影剂的理想化剖视图;
[0024]图3根据本发明的一些实施方式,以流程图的形式描绘了制备靶向性MRI造影剂的方法;
[0025]图4根据本发明的一些实施方式,描绘了用于将靶向性部分粘附到纳米粒子的合成途径;
[0026]图5根据本发明的一些实施方式,描绘了聚乙烯亚胺(PEI)涂层纳米粒子,其具有许多可偶联到N-乙酰化肽的可用仲胺;
[0027]图6根据本发明的一些实施方式,为MRI造影剂的显微图,所述MRI造影剂包含以共价键结合到PEI-涂层纳米粒子并被施用到用Cell Tracker Green染料染色的吞噬细胞的NHS酯-Cypher5E染料;和
[0028]图7根据本发明的一些实施方式,为用荧光素标记的AESTYHHLSLGYMYTLN-NH2培养后的RKO细胞的显微图。
具体实施方式
[0029]在一些实施方式中,本发明涉及用于磁共振成像(MRI)的新型靶向性造影剂。本发明也涉及制备该靶向性MRI造影剂的方法和使用该MRI造影剂的方法。通常,这种靶向性MRI造影剂提供增强的弛豫度、改善的信噪比、靶向性和抗凝聚性。制备这种MRI造影剂的方法通常提供更好的粒度控制,并且使用这种MRI造影剂的方法通常提供提高的血清除率和生物分布。
1.靶向性核/壳纳米粒子基MRI造影剂
[0030]通常,本文描述的靶向性MRI造影剂是基于核/壳纳米粒子。因此,在一些实施方式中,本发明涉及靶向性造影剂,其包含:(a)无机基磁芯;(b)有机基非磁性涂层,该非磁性涂层分布在所述无机基磁芯周围并连接在该无机基磁芯上,从而在整体上,所述磁芯和所述非磁性涂层形成了核/壳纳米粒子;和(c)粘附在所述核/壳纳米粒子上的标靶物,从而在整体上,所述核/壳纳米粒子和所述标靶物形成了靶向性MRI造影剂。
[0031]在一些涉及靶向性MRI造影剂的实施方式中,上述的无机基磁芯包含的材料选自过渡金属、合金、金属氧化物、金属氮化物、金属碳化物、金属硼化物以及它们的组合。在一些这样的实施方式中,无机基磁芯包含超顺磁性材料。在一些这样的实施方式中,无机基磁芯包含氧化铁。虽然组成这种无机基材料的材料不被特别限制,但当这种磁芯用作造影剂时,其通常必须包含适合提高MRI的材料。这种无机基磁芯通常为纳米粒子并且通常包含小于约100nm、特别是约小于50nm、和更特别约小于30nm的直径。本发明中使用的,术语"无机基"是指主要不是烃的材料。通常,这排除了聚合材料。
[0032]在一些涉及靶向性MRI造影剂的实施方式中,上述的有机基非磁性涂层包含聚合物涂层。在一些这样的实施方式中,聚合物涂层包含硅烷改性的聚乙烯亚胺(PEI)。在一些或其它的涉及靶向性MRI造影剂的实施方式中,上述的有机基非磁性涂层包含非聚合物涂层。在这样一些后者的实施方式中,非聚合物涂层为氨丙基硅烷。通常,这些涂料是具有官能团的,由于它们允许标靶物直接或通过连接体粘附。注意,本发明中使用的术语"有机基"被用于描述烃基物,其中,所述烃可被取代以进一步包括一个或多个官能团部分(例如,卤素、氨基、硅烷基团等)。在一些实施方式中,这种有机基非磁性涂层被选择使得它们能够允许多配体偶联和/或使所获得的核/壳纳米粒子的直径不会增加到超出无机基磁芯直径太多。在一些或其它实施方式中,有机基非磁性涂层提供对纳米粒子核的稳定性并且允许引入治疗剂。
[0033]如上所述,靶向性MRI造影剂包含核/壳纳米粒子。参考图1,描绘的理想化的核/壳纳米粒子100包含核101和壳102。这种核/壳纳米粒子通常具有约小于100nm的复合直径。所属领域的技术人员应理解这种球面表示是理想化的并且这种核/壳纳米粒子通常具有不规则的形状。在一些这样的实施方式中,这种核/壳纳米粒子为单分散性的。另外,在一些实施方式中,所述壳可被看作包含了多层子壳,即多层壳。示例性的这种核/壳纳米粒子在Bonitatebus等人的美国专利No.6,797,380和Bonitatebus等人的美国专利No.10/208,945中描述。
[0034]如上所述,除了核/壳纳米粒子之外,靶向性MRI造影剂进一步包含标靶物,其中所述标靶物被粘附到核/壳纳米粒子上。通常,这种粘附包括共价键联(尽管非共价粘附也是允许的),并且这种靶向性MRI造影剂的示例性实施方式描绘在图2中。现在参考图2,这种靶向性MRI造影剂200包含在图1中描绘的核/壳纳米粒子100和通过连接体202粘附到核/壳纳米粒子100的壳102上的标靶物201。
[0035]通常,标靶物为配体或其他将MRI造影剂导向到特异性器官或病变位置的部分。在一些实施方式中,靶向分子为肽。适合的肽包括AEPVYQYELDSYLRSYY(序列标识号:1)、AEFFKLGPNGYVYLHSA(序列标识号:2)、AELDLSTFYDIQYLLRT(序列标识号:3)、AESTYHHLSLGYMYTLN(序列标识号:4)以及它们的组合,但不限制于此。在一些或其它实施方式中,靶向分子选自蛋白质、低聚核苷酸;小的有机分子、肽核酸以及它们的组合。
[0036]在一些实施方式中,标靶物通过连接体例如1-乙基-3-(3-二甲基氨丙基)碳二亚胺盐酸(EDC)粘附到核/壳纳米粒子上。该连接体可包含通过第一部分将标靶物粘附到纳米粒子的任何连接部分。该连接体可象一个碳原子一样短,或为长的聚合物,例如聚乙二醇,聚赖氨酸或其它通常用在制药业上以调整造影剂的药物动力学和生物分布特征的聚合物。其他不同长度的连接体包括具有选自氧、硫、氮和磷中的一种或多种杂原子及任选地以卤原子取代的C1-C250长度。在具体的实施方式中,所述连接体,单独地或以其组合的形式,包含至少一种由天然或合成的单体构成的低聚或聚合的物质、选自药理学上可接受的低聚物或聚合物组合物的低聚或聚合的部分、低聚-或聚-氨基酸、肽、糖类、核苷酸和具有1-250个碳原子的有机部分。具有1-250个碳原子的有机部分可包含一个或多个杂原子例如氧、硫、氮和磷并且可在一个或多个位置任选地以卤原子取代。
[0037]所述第一部分可为连接体的延伸部分,其由连接体上的活性物质与纳米粒子上的活性基团反应而形成。活性物质和活性基团的例子包括活性酯(例如N-羟基琥珀酰亚胺酯,五氟苯基酯)、碳二亚胺、亚磷酰胺、异氰酸酯、异硫氰酸酯、醛、酰氯、磺酰氯、马来酰亚胺、卤代烷、胺、膦、磷酸酯、醇、羧酸或硫醇,但不被限至于此,前提是活性物质和活性基团是匹配的,以经历产生共价连结的偶联的反应。
2.制备基于核/壳纳米粒子的靶向性MRI造影剂的方法
[0038]在一些实施方式中,制备上述靶向性MRI造影剂的方法包含以下步骤:a)合成纳米粒子的核301;b)合成纳米粒子壳以使纳米粒子核基本上被所述壳302覆盖;和c)如图3中描绘的,将标靶分子粘附到纳米粒子303的壳上。
[0039]在一些实施方式中,无机基磁芯通过提高的结晶度具有改善的磁化强度。所述提高的结晶度很大程度上取决于核是如何制造。控制核的粒度通过以下方式完成,例如,通过控制金属氧化物核的粒度和粒度分布以及通过使用已知长度的预聚物控制壳的厚度。例如,磁性金属氧化物核可通过稳定的表面活性剂壳的低聚反应/聚合反应和共价粘附聚合物链到稳定的表面活性剂壳上而被稳定和防止凝聚。这种涂层化学允许控制极性,电荷,响应的性质和用于具体位置和目的粒子的设计的灵活性。
3.使用基于核/壳纳米粒子的靶向性MRI造影剂的方法
[0040]在一些实施方式中,本发明涉及使用上述靶向性MRI造影剂的方法。在一些这样的实施方式中,造影剂向体外细胞施用,并且该造影剂向所述细胞的施用受到监视。在一些这样的实施方式中,造影剂向体内受体施用,并且该造影剂向受体的施用同样受到监视。在这样一些后者的实施方式中,监视所述造影剂的施用通过成像技术实现,所述成像技术包括但不限于MRI、光学成像(包括光学相干断层成像)、计算机断层成像、正电子发射断层成像以及它们的组合。
[0041]通过利用生物识别方法,靶向性MRI造影剂可被受体导向以在靶向位点集中该造影剂,从而放大靶向位点的信号并且增强该区域的成像。在一些实施方式中,这会允许将新型MRI造影剂具体靶向到涉及尿激酶受体(uPAR)上调(up-regulation)的疾病位置或其他用于诊断的分子成像或治疗的疾病生物标志物。疾病生物标志物包括但不限于肽、蛋白质、小的分子和核酸。将对于uPAR特异的肽(即,标靶物)粘附到核/壳纳米粒子上允许将MRI造影剂靶向到由uPAR上调的区域表征的疾病位置。纳米粒子粘附的对于uPAR特异的肽也能够抑制uPA:uPAR连接到副纤维连接蛋白或整联蛋白。具体地讲,肽AESTYHHLSLGYMYTLN(序列标识号:4)能够连接uPAR并且抑制整联蛋白的连接(美国专利No.6,794,358)。肽AEPVYQYELDSYLRSYY(序列标识号:1)、AEFFKLGPNGYVYLHSA(序列标识号:2)、AELDLSTFYDIQYLLRT(序列标识号:3)能够连接uPAR并且抑制副纤维连接蛋白的连接(美国专利No.6,794,358)。另外,尿激酶型纤溶酶原活化剂和尿激酶型纤溶酶原活化剂受体将纤溶酶原转变成纤溶酶,所述纤溶酶是造成局部细胞表面蛋白水解活性的原因(Ellis等人,J.Biol.Chem.,264:2185-2188(1989))。这会在正常细胞和肿瘤细胞的迁移期间发生。
[0042]MRI造影剂的摄入可通过成像监视,所述成像可诊断的几种疾病包括但不限于癌和炎症性疾病例如风湿性关节炎(RA)、慢性阻塞性肺病(COPD)和多发性硬化症(MS)。
[0043]如本文所述,制备靶向性MRI造影剂的方法提供了基于核/壳纳米粒子的靶向性MRI造影剂,其包含以下的任何组合:非聚集结构,非聚集晶体,各粒子的均匀且增强的磁性,较长的血半衰期和通过小的开口获取(access)非网状内皮系统(RES)的一部分的器官和组织的成像,选择用作血池剂或位点特异性的造影剂,用于水分扩散以及水分子更接近提高信号强度和对比度的超顺磁性氧化物(SPMO)核的更大的有效体积,提高的靶向性能和疾病早期阶段的发现。
[0044]下列包括的实施例用以阐述本发明的具体实施方式。本领域的技术人员应理解描述在以下实施例中的方法仅代表本发明的示例性实施方式。然而,本领域的技术人员应理解根据本发明公开的内容可对本发明描述的具体实施方式进行多处改变并且还可获得同样或类似的结果,只要不脱离本发明的主旨和范围。
实施例1
[0045]该实施例说明SPIO纳米粒子的合成和表征以及PEI-硅烷涂层的SPIO纳米粒子的制备。
[0046]5nm SPIO纳米粒子的合成。一个25ml、3颈的Schlenk烧瓶配有冷凝器,在顶部130mm叠堆有Vigreux塔,以及热电偶。所述冷凝器配有氮气入口并且氮气流过该系统。Schlenk烧瓶和Vigreux塔用玻璃绒隔热。将三甲胺-N-氧化物(Aldrich,0.570g,7.6mmol)和油酸(Aldrich:99+%,0.565g,2.0mmol)分散到10mL的二辛醚(Aldrich:99%)中。将所述分散体以约20℃/分钟的速率加热到80℃。一旦混合物达到约80℃,将265μL的Fe(CO)5(Aldrich:99.999%,2.0mmol)通过Schlenk接头迅速地注入搅拌的溶液中。所述溶液瞬时变成黑色,伴有剧烈的白“烟”生成。将溶液迅速地加热到约120-140℃。在6-8分钟内将反应罐冷却到100℃,保持在该温度下并搅拌75分钟。在约100℃下搅拌75分钟后,将温度以约20℃/分钟的速率增加到约280℃。在将溶液搅拌75分钟后,除去加热炉和玻璃绒使所述反应恢复到室温。一旦达到室温,将一份等分试样移除并将其溶解入甲苯中以用于使用动态光散射(DLS)的粒度测量、使用透射电镜(TEM)的影像分析和使用X射线能谱(EDX)的元素分析。
[0047]为了制备用于振动样品磁强计分析和元素分析的样本,将大约5-10mL的原始反应溶液添加到20mL的异丙醇中,并且将所述溶液在3000rpm下离心分离10分钟。将上层清液轻轻倒出,再添加另外的20mL的异丙醇,并且再次通过离心法收集沉淀。将沉淀的氧化铁纳米粒子进行整夜风干,产生黑色磁性粉末。
[0048]饱和磁化强度。使用振动样品磁强计(VSM)测量沉淀的SPIO纳米粒子的饱和磁化强度(Msat)。在磁性粉末上进行元素分析以确定Fe的浓度,并且以对于每个样品Msat以emu/g Fe的单位计算。已知用于批量γ-Fe2O3和Fe3O4的Msat已知分别为约104emu/g Fe和约127emu/g Fe。虽然一些反应产生的SPIO剂的Msat值低于100emu/g Fe,但对于公开的SPIO剂的Msat值通常范围为约100emu/g Fe到约120emu/gFe(表1)。
表1:饱和磁化强度,Msat
平均尺寸(nm) | Msat(emu/gFe) |
4.80 | 116.60 |
5.46 | 124.30 |
4.58 | 83.60 |
5.00 | 123.20 |
4.60 | 84.68 |
3.95 | 101.57 |
4.92 | 97.40 |
4.25 | 99.01 |
[0049]PEI-硅烷涂层的SPIO纳米粒子的制备。在包含具有3.25mgFe/mL的5nm SPIO的四氢呋喃(4.0mL,13mg Fe,0.232mmol)的瓶中添加四氢呋喃(10mL),接着加入含有50%PEI硅烷的异丙醇(2.0mL),并对获得的浑浊液进行超声波降解2小时。然后添加异丙醇(4.0mL)并且对所述溶液超声波降解另外16小时。然后添加浓缩的NH4OH(1.0mL,14.8mmol)并且在室温下将所述溶液搅拌4小时。然后用H2O(10mL)对溶液进行稀释并用己烷(3x10mL)和油酸(etoleic acid)(3x10mL)进行萃取。在真空中除去任何在水层中残余的有机物。获得的均匀的水溶液通过200nm注射过滤器,接着通过100nm注射过滤器。然后用H2O(10mL总体积)对溶液进行稀释并且使用100kDa MW截止滤波器(2680xg直到约3mL的残余溶液)纯化。离心过滤方法总共进行了6次。如果需要,使用浓盐酸将所述溶液的最终pH值调节到约7.4至约7.7。
实施例2
[0050]这个实施例说明将肽粘附到PEI涂层的硅氧烷核/壳纳米粒子上的方法。利用EDC聚乙烯亚胺涂层的硅氧烷核/壳纳米粒子可被结合到N-乙酰化肽。如图4的合成方案所述,所述反应在0.1M MESpH4.5-5下发生。聚乙烯亚胺(PEI)涂层的核/壳纳米粒子具有许多可偶联到N-乙酰化肽的可用的仲胺,所述N-乙酰化肽具有的结合数量可被控制以获取对于生物标靶的最高结合率,如图5所述。
实施例3
[0051]该实施例是细胞摄入研究的说明。NHS酯-Cypher5E染料以共价键连接到PEI涂层的纳米粒子上。这些胺-偶联染料显示了这些纳米粒子摄入到噬菌细胞内并且通过使用NHS酯化学(类似对于肽偶联化学,等)证明了用于粘附的PEI涂层的游离胺的效用。肽可以类似的方式被偶联到这些粒子以摄入到非吞噬的疾病特异性细胞中,所述非吞噬的疾病特异性细胞表示用于诊断的所关注的生物标志物。根据本发明的一些实施方式,图6为MRI造影剂的显微图,所述MRI造影剂包含以共价键结合到PEI-涂层纳米粒子并被施用到用Cell Tracker Green染料染色的吞噬细胞的NHS酯-Cypher5E染料。
[0052]为了治疗或诊断目的,肽-官能化的阳离子纳米粒子也可将低聚核苷酸运送到疾病特异性位置。
实施例4
[0053]该实施例说明了用于靶向uPAR的肽的设计和合成。接合uPAR的肽可来自多种来源,包括可连接uPAR或例如Phage Display的组合库的蛋白质的肽片段。所述连接也可潜在地抑制uPAR的活性,因此为抑制剂。这种肽的例子为整联蛋白片段AEPVYQYELDSYLRSYY-NH2(WO97/35969)。因为具有标准的肽化学,上述序列可通过使用固相肽合成法,在N-端(N-terminus)引入标记而合成。可将所述标记粘附到上述的序列中的丙胺酸A上。
[0054]利用标准的固相技术,使用25μmol量的2,4-二甲氧基二苯甲基胺树脂(Rink AmideAM)将肽与Nα-Fmoc-保护的氨基酸进行合成(Fmoc=芴甲氧羰基)。所述肽使用Rainin/Protein Technology Symphony固相肽合成器(Woburn,MA)合成。在任何化学之前,将树脂在二氯甲烷中溶胀一个小时,并且随后用DMF(二甲基甲酰胺)交换超过半小时或更长。各偶联反应在具有5当量的氨基酸的DMF中于室温下进行。反应时间通常为45分钟,对于预期难以偶联的残余物反应时间为1小时(例如,在IPP序列中将异亮氨酸I偶联到脯氨酸P)。使用的偶联剂为HBTU(邻-苯并三唑基-1-基-N,N,N’,N’-四甲基脲六氟磷酸酯),其基底为NMM(N-甲基吗啉)。对于每个步骤,所述偶联剂以相对于估计的树脂容量5当量的量被施用,并且所述反应在2.5mL在DMF中的0.4M NMM溶液中进行。所述反应没有干扰氨基酸的侧链,如果活性基团存在,所述侧链通常用酸不稳定基团进行保护。通常,酪氨酸、苏氨酸和丝氨酸侧链作为相应的叔-丁基醚被保护。谷氨酸侧链作为相应的叔-丁基酯被保护。赖氨酸和鸟氨酸侧链被Boc保护。谷氨酸盐侧链作为γ-三苯甲基衍生物被保护和精氨酸侧链作为2,2,5,7,8-五甲基-苯并二氢吡喃-6-磺酰基衍生物被保护。
[0055]以下的各偶联反应,N-端Fmoc-保护的胺通过在室温下二次施加在DMF中的20%哌啶约15分钟而脱保护(deprotected)。在增加最后的残余物后,仍在肽合成器上的所述树脂用DMF和二氯甲烷彻底地漂洗。
[0056]为了将荧光素染料例如5(6)-羧基荧光素偶联到肽的N-端,以与氨基酸同样的方式将所述染料HBTU和NMM添加到树脂中。在反应后,该树脂用DMF和二氯甲烷彻底地漂洗并在氮气流下干燥。对于肽配体,荧光素染料通过氨基酸序列KKGG(K=赖氨酸,G=甘氨酸)粘附到肽的N-端,其除了柔性之外还提供溶解度。就用于抗体靶向生成的肽而言,荧光素由羧基生物素取代。
[0057]为了将肽从树脂分离,使用由1mL TFA、2.5%TSP(三异丙基硅烷)和2.5%水组成的混合物。在室温下将树脂和混合物搅拌约3到4小时。使用玻璃绒将树脂小珠滤出,接着用2-3mL的TFA漂洗。将肽用40mL冰冷的醚沉淀并以3000-4000rpm离心分离直到沉淀物在离心管底部形成颗粒。将醚轻轻倒出,将颗粒再次悬浮在冷的醚(40mL)中并再次离心分离;将该方法重复2-3次。在最后漂洗期间,将10mL的净化水(例如通过Analyzer Feed System生产的净化水)添加到30mL的冷醚中,并且将所述混合物再次离心分离。将醚轻轻倒出。将包含粗肽的水层转移到用于冷冻干燥的圆底烧瓶中。对于肽合成的粗产率通常为约90%。通常未观察到未标记的肽。
[0058]通过在具有20%DMSO的水溶液(1mg/2-3mL)中将包含半胱氨酸的粗肽搅拌一整夜而产生环肽。
[0059]肽使用C4-二氧化硅柱(Vydac,Hesperia,CA)通过反相半制备或制备的HPLC进行纯化。在220nm处监视肽色谱,该数值对应于酰胺发色团的吸收。为了确保荧光素染料在肽上的存在,也在495nm处观测。用于半制备和制备的CH3CN/TFA(乙腈/三氟乙酸;100:0.01)和H2O/TFA(水/三氟乙酸;100:0.01)洗脱剂的溶剂体系以3mL/分钟和10mL/分钟的流动率分别被使用。溶解在纯化水中(例如由Millipore′sAnalyzer Feed System制备的)的粗肽分别以1.5mg和5-10mg肽的量被注入以进行半制备或制备。分析色谱形状以确保良好的分辨率和峰形。所有肽的梯度条件通常为CH3CN/TFA(100:0.01)在30分钟内从5%至50%。纯化的肽通过基质辅助激光解吸飞行时间质谱法确定。肽环化通常导致使用HPLC的保留时间的改变和使用MALDI-TOF的不同质量。
实施例5
[0060]该实施例说明在癌细胞系RKO(ATCC CRL2577)中uPAR特异性的肽的筛选。过度表达(overexpress)uPAR的RKO癌细胞在6孔板中被在适当的介质中培养到>80%的汇集(confluence)。在充足的介质中添加不断增加浓度(0-0.15nM)的荧光素-标记的肽到的活细胞中并培养6小时。培养之后,用胰酶将细胞从孔中移除,用1mL磷酸酯缓冲生理盐水洗涤3次并使用1%的戊二醛固定。然后将细胞放置在盖玻片上以使用共聚焦显微镜进行分析。图7为用荧光素标记AESTYHHLSLGYMYTLN-NH2培养后的RKO癌细胞放大80倍的显微图。
[0061]在至少0.015nM浓度的肽下接收uPAR肽的细胞具有可观测的肽到所有细胞的连接。作为另外一种选择,本领域的技术人员可利用更高通量的光学分析仪(InCell1000,Amersham Bioscience/GEHC)在96孔板中测量荧光分子的摄入。
实施例6
[0062]该实施例说明用于标靶其他生物标志物的肽的设计和合成。在Wadih Arap、Renata Pasqualini、Erkki Ruoslahti、SCIENCE279:377(1998年1月16日)中可找到计结合整联蛋白αvβ3的肽的例子,其中,使用噬菌体显示库的肽序列的体内选择被用于隔离特别深入肿瘤血管的那些肽。这些肽中的二个,一个为包含av整联蛋白结合的Arg-Gly-Asp基序,另一个为在肿瘤血管中有效地标靶αvβ3的Asn-Gly-Arg基序。
[0063]用于标靶其他生物标志物的肽序列可使用上述方法合成。
实施例7
[0064]该实施例说明基于核/壳纳米粒子的靶向性MRI造影剂超过现有技术的优点。
[0065]对于核/壳纳米粒子的分析数据,如表2所示,包括水力粒径(hydrodynamic size)、表面电荷、对于包含Si的纳米粒子的Si/Fe质量比、以及在本文描述的多种核/壳粒子的弛豫率值(R1,R2和R2/R1)。DH的测量,表面电势(ζ)和Si/Fe质量比(对于具有硅烷基涂层的样品)是确定整批的质量和纯度的标准分析。
表2:用于5nm涂层SPIO造影剂的分析数据
壳 | DH(nm) | R1(mM-1s-1) | R2(mM-1s-1) | R2/R1 |
PEI-硅烷 | 13.8±1.4 | 14.5 | 48.2 | 3.3 |
[0066]凝聚。一种用于测量纳米粒子凝聚的分析参数为在水溶液中通过动态光散射(DLS)测量的水力粒径。对于5nm SPIO PEI-硅烷涂层的粒子,DH值大于约30nm表明了粒子凝聚。使用PEI硅烷对5nm粒子的官能化导致了涂层纳米粒子的水合直径小于15nm和分散性小于10%。将靶向分子进一步加入到该涂层的纳米粒子将导致粒径的增加,该粒径包括但不限于达到25-30nm。在一个实施方式中,最终官能化和标靶的纳米粒子的直径为小于30nm以及分散性为约10%。
[0067]弛豫率。非官能化的5nm SPIO PEI-硅烷涂层的粒子的R2/R1比率为3.3。该值表明了具有T1和T2性质的造影剂并证明了增加的弛豫率超过了现有技术中描述的粒子。
[0068]靶向性。通过使用涂层纳米粒子上可用的官能度,靶向分子可被粘附到疾病的特异性标志上以靶向该粒子到所关注的疾病位置。例如,将纳米粒子靶向到过度表达尿激酶受体(uPAR)的肿瘤可提供关于生物活性和成像后的肿瘤位置的基本信息。为了完成这一点,通过如上所述的方法将靶向分子粘附到涂层纳米粒子上并保持其能够特别紧密地连接(Kd<1mM)到标靶物的能力。
[0069]血液清除和生物分布。非凝聚的、单分散性、直径小于30nm的靶向纳米粒子,其优选具有在人体内小于12小时但大于1小时的血半衰期。这可在所关注的位置(疾病位置)提供最大的摄入,并由于留在血管中的粒子而降低了背景信号。这些靶向纳米粒子的物理特性应允许粒子逃避RES并有效地标靶所关注的位置。更小的尺寸(约30nm)和单分散性应允许粒子分布在人体内,并且不会在积聚在疾病位点前非特异性地的到达肝脏和脾。
[0070]信号。将靶向纳米粒子施用到受体后,成像将在施用后几小时的最佳时间点进行。这样,使用优化的成像方案将观察到由于纳米粒子的积聚而引起的信号改变。在一个实施例中,成像可在注入后24小时进行。在这个时间点,残余纳米粒子在血液中将不再被发现并且标靶的纳米粒子将停留在疾病位置(即动脉粥样硬化病变,肿瘤或其他)。使用T2-特异性脉冲序列进行成像,在其生成的图像中,积聚的粒子将导致低于周围组织的背景信号超过10%的净信号损失。这将提供需要的临床资料。
实施例8
[0071]该实施例说明了治疗剂通过官能化纳米粒子的运送,其中肽-官能化阳离子纳米粒子将低聚核苷酸运送到用于治疗目的的疾病特异性位置。在这个实施例中,具有官能团外壳例如聚乙烯亚胺(PEI)的阳离子纳米粒子可利用可用的官能团共价粘附靶向分子,而不完全中和阳离子表面。然后可将游离的低聚核苷酸添加到靶向阳离子纳米粒子中。正表面电荷将允许带负电荷的低聚核苷酸的可逆结合。在形成靶向复合物的基础上,所述复合物可施用到细胞或哺乳动物的受体。标靶的复合物将定位所关注的的细胞标靶物,并且在复合物内部作用的基础上,释放低聚核苷酸以运送到所述细胞。
实施例9
[0072]该实施例说明将基于核/壳纳米粒子的靶向性MRI造影剂施用到体内受体。动物可被磁共振成像扫描以产生鼠解剖的“预注入”T2-加权MR图像。所关注的特异性区域(ROI)是肝脏。然后无菌的基于核/壳纳米粒子的靶向性MRI造影剂通过鼠尾静脉注射被施用到雌性Sprague-Dawley鼠,注射剂量为总注射量600毫升中1mg Fe/kg体重或5mg Fe/kg体重的剂量。
实施例10
[0073]该实施例说明如何监视在体内的基于核/壳纳米粒子的靶向性MRI造影剂。在基于核/壳纳米粒子的靶向性MRI造影剂的初始施用后,动物被转移到笼中24小时,然后再次成像以产生鼠解剖的“注射后”T2-加权MR图像。肝脏被作为所关注的区域(ROI)并且获得了几个图像。
[0074]应当理解上述实施方式的一些上述结构、功能和操作对于实现本发明不是必要的,它们被包含在说明书中仅为了示例性实施方式的完整。另外,应当理解在上述参考的专利和出版物中提出的具体结构、功能和操作可结合本发明进行实现,但是它们对于本发明的实现不是必要的。因此,应当理解,只要不实际偏离由所附权利要求限定的本发明的主旨和范围,本发明可以以具体描述的以外的方式实现。
Claims (23)
1.一种靶向性MRI造影剂,其包括:
a)一种无机基磁芯;
b)一种有机基非磁性涂层,其包含硅烷,所述非磁性涂层分布在所述无机基磁芯周围并连接在该无机基磁芯上,从而在整体上,所述磁芯和所述非磁性涂层形成了核/壳纳米粒子;和
c)一种粘附在所述核/壳纳米粒子上的标靶物,从而在整体上,所述核/壳纳米粒子和所述标靶物形成了靶向性MRI造影剂。
2.根据权利要求1所述的靶向性MRI造影剂,其中,所述无机基磁芯包含的材料选自过渡金属、合金、金属氧化物、金属氮化物、金属碳化物、金属硼化物以及它们的组合。
3.根据权利要求1所述的靶向性MRI造影剂,其中所述无机基磁芯包含超顺磁性材料。
4.根据权利要求3所述的靶向性MRI造影剂,其中所述无机基磁芯包含式[Fe2 3+O3]x[Fe3 3+O4]1-x表示的氧化铁,其中1≥x≥0。
5.根据权利要求4所述的靶向性MRI造影剂,其中所述无机基磁芯的Msat值为对于5nm无机基磁芯至少约60emu/g Fe。
6.根据权利要求1所述的靶向性MRI造影剂,其中所述硅烷选自硅烷改性的聚乙烯亚胺、氨丙基硅烷、2-羧基乙基硅烷、N-碘乙酰基氨丙基硅烷、3-异氰酸丙酯基硅烷(3-isocyanatopropylsilane)、5,6-环氧己基三乙氧基硅烷、3-异硫氰酸丙酯基硅烷(3-isothiocyanatopropylsilane)和3-叠氮丙基硅烷。
7.根据权利要求1所述的靶向性MRI造影剂,其中所述有机基非磁性涂层为聚合物。
8.根据权利要求7所述的靶向性MRI造影剂,其中所述聚合物包含硅烷改性的聚乙烯亚胺。
9.根据权利要求1所述的靶向性MRI造影剂,其中所述有机基非磁性涂层为非聚合物。
10.根据权利要求9所述的靶向性MRI造影剂,其中所述非聚合物为氨丙基硅烷。
11.根据权利要求1所述的靶向性MRI造影剂,其中所述核/壳纳米粒子的水力直径为至少约100nm。
12.根据权利要求1所述的靶向性MRI造影剂,其中所述核/壳纳米粒子的水力直径为至少约50nm。
13.根据权利要求1所述靶向性MRI造影剂,其中所述核/壳纳米粒子的水力直径为至少约30nm。
14.根据权利要求1所述的靶向性MRI造影剂,其中所述标靶物直接地通过共价键或通过连接体的方式粘附到所述核/壳纳米粒子上。
15.根据权利要求1所述的靶向性MRI造影剂,其中所述标靶物选自肽、蛋白质、低聚核苷酸;小的有机分子、肽核酸以及它们的组合。
16.根据权利要求15所述的靶向性MRI造影剂,其中所述肽选自AEPVYQYELDSYLRSYY(序列标识号:1)、AEFFKLGPNGYVYLHSA(序列标识号:2)、AELDLSTFYDIQYLLRT(序列标识号:3)、AESTYHHLSLGYMYTLN(序列标识号:4)、以及它们的组合。
17.根据权利要求1所述的靶向性MRI造影剂,其中所述靶向性MRI造影剂通过包含以下步骤的方法制备:
a)合成纳米粒子的核;
b)合成纳米粒子的壳以使所述纳米粒子核基本上被所述壳覆盖;和
c)将标靶分子粘附到所述纳米粒子的壳上。
18.一种包含以下步骤的方法:
a)提供一种组合物,其包含:
i)无机基磁芯;
ii)有机基非磁性涂层,该有机基非磁性涂层选自硅烷改性的聚乙烯亚胺和氨丙基硅烷,其分布在所述无机基磁芯周围并连接在无机基磁芯上,从而在整体上,所述磁芯和所述非磁性涂层形成了核/壳纳米粒子;和
iii)粘附在所述核/壳纳米粒子上的标靶物;和
b)将所述组合物用作MRI造影剂。
19.根据权利要求18所述的方法,其中所述造影剂被施用到体外细胞。
20.根据权利要求19所述的方法,其中所述造影剂到所述细胞的施用受到监视。
21.根据权利要求18所述的方法,其中所述造影剂被施用到体内受体。
22.根据权利要求21所述的方法,其中所述造影剂到所述受体的施用受到监视。
23.根据权利要求22所述的方法,其中监视所述造影剂的施用通过成像技术实现,所述成像技术选自MRI、光学成像、光学相干断层成像、计算机断层成像、正电子发射断层成像以及它们的组合。
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CN101843907A (zh) * | 2010-04-20 | 2010-09-29 | 上海纳米技术及应用国家工程研究中心有限公司 | SPIO@SiO2-WGA肠壁靶向造影剂的制备方法 |
CN105462580A (zh) * | 2015-11-19 | 2016-04-06 | 上海纳米技术及应用国家工程研究中心有限公司 | 一种荧光靶向的锌掺杂四氧化三铁纳米颗粒及制备 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101843907A (zh) * | 2010-04-20 | 2010-09-29 | 上海纳米技术及应用国家工程研究中心有限公司 | SPIO@SiO2-WGA肠壁靶向造影剂的制备方法 |
CN107969116A (zh) * | 2015-06-10 | 2018-04-27 | 韩国基础科学支持研究院 | 亲水性颗粒、其制造方法及使用该颗粒的造影剂 |
CN105462580A (zh) * | 2015-11-19 | 2016-04-06 | 上海纳米技术及应用国家工程研究中心有限公司 | 一种荧光靶向的锌掺杂四氧化三铁纳米颗粒及制备 |
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WO2007069040A3 (en) | 2008-08-21 |
US20070140974A1 (en) | 2007-06-21 |
JP2009519316A (ja) | 2009-05-14 |
WO2007069040A2 (en) | 2007-06-21 |
EP1960003A2 (en) | 2008-08-27 |
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