CN1909931B - 用于分子成像的超声造影剂 - Google Patents
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Abstract
本发明提供了一种包括金属纳米颗粒的新型造影剂以及利用该造影剂的成像方法。该金属纳米颗粒是稳定、生物相容和可以与用于靶向可视化的生物靶向特异性分子耦合。
Description
本发明涉及一种用于超声波检查法和超声成像尤其是分子成像的新型造影剂(UCA)以及使用该造影剂成像的方法。
在过去的15年中已研发出一些安全和实用的超声造影剂(UCA)。大多数这些造影剂基于充气的微泡,它们强化了多普勒信号。所述壳体是蛋白质、脂质、表面活性剂或聚合物,且它们具有几个微米的粒度,使得它们能够通过肺。此外,基于泡的UCA是可压缩的,这导致非线性的性质,即它们在临床研究中通常使用的超声波的特定频率下共振。
尽管已经证实微泡剂是有用的,但是它们具有显著的局限性,例如它们有限的使用寿命和难于将它们靶向到特定器官。
为了解决这些缺点,已经研发出由壳体包封的液滴组成的UCA。Hall C.S.等人(2000,J.Acoust。Soc.Am.108(6):3049-3057)已经研究了250nm的脂质包封的(非气态)全氟化碳乳液液滴在超声成像中的效率。这些颗粒可以通过抗体靶向到组织中从而提供额外的分子信息。
理想地,超声造影剂应当具有尽可能多的下列特征:
-在血液中稳定和有充分的使用寿命,例如在30分钟或者更多时间内允许在靶向器官中进行检测;
-低于8微米的粒度,使它们能够通过毛细血管;
-无毒性或者可接受的毒性
-足够的反射增强
-易于制备和临床使用
-允许高度特异靶向
此外,超声造影剂应当优选能与现有的超声成像系统(例如PhilipsUltrasound Imaging System)一起使用。
已经研发出不同的包括具有磁性的金属或者金属氧化物的颗粒用作磁共振成像(MRI)的造影剂。US 5310539公开了包括黑色素和不可离解的诱发信号的金属的组合的图像强化剂,其中诱发信号的金属优选是磁性或者顺磁性金属。US 2002/0136693记载了用于诊断目的的试剂,其包括含有磁性双金属氧化物/氢氧化物或者磁性金属的磁性颗粒和任选的配合剂。US 2003/0082237记载了这样的纳米颗粒:其被构造成通过嵌段共多肽(copolypetide)或者均聚物聚电解质的具有内层和外层囊泡的球体。纳米颗粒的外层或内层可以包括金属或者金属氧化物,其任选进行官能化,用于位点选择性的医学成像。
WO 02/11771记载了作为超声造影剂的聚集在蛋白质上的金属纳米颗粒。在几种颗粒聚集在一种蛋白质上时,聚簇本身通过超声波被检测到并提供高的本底和低的信燥比。Bekeredjian等人记载了金包裹的微管作为超声造影剂的潜在用途(2002,Ultrasound inMed.&Biol.28(5):691-695)。这种金包裹的微管显示出相对于常规造影剂(微泡)更持久的造影活性。但是,绝对强度通常更低。
本发明提供了包括金属纳米颗粒的新型造影剂。这些颗粒在聚集时由于它们与身体组织的强烈声阻抗差异而成为声学反射体,且具有优于现有商业UCA(微泡)的优势稳定和可以如现有的靶向造影剂相同方式进行改性的优势。已经表明,用这些纳米颗粒获得薄膜时,就得到了反射增强。造影剂可以和所有形式的超声波检查法(例如B模式、多普勒频移超声波检查法等)一起使用。
这样,本发明涉及包括金属纳米颗粒的造影剂,该纳米颗粒具有大于35·105g/cm2s、特别是大于50·105g/cm2s的声阻抗。
更具体而言,根据本发明,所述造影剂包括无毒和化学稳定的金属纳米颗粒。
更具体而言,根据本发明,所述金属纳米颗粒优选具有1nm-100nm、特别是1nm-50nm的直径。
本发明的造影剂包括经涂覆的例如经聚合物涂覆的金属纳米颗粒。
此外,所述用作根据本发明的造影剂的金属纳米颗粒是靶向的,即它们包括生物靶向剂例如细胞、组织、微生物,例如寄生物,或者生物分子例如蛋白质、DNA或RNA特异性靶向剂,其中抗体或其片段仅为一个实例。
此外,本发明的金属纳米颗粒可以通过用治疗剂涂覆颗粒或通过在涂层中引入药物而用于施用。
本发明的具体实施方案涉及包括金属纳米颗粒的造影剂,其中所述金属是非磁性金属。根据另一实施方案,所述金属颗粒包括下列金属,该金属为贵金属或者一种或多种贵金属的混合物,例如金、银、铂、钯、钨或钽、铼。根据本发明的更加具体的实施方案,所述金属纳米颗粒由金制得。任选地,该金属颗粒包括金属氧化物或者具有稳定的氧化物薄层或者可以具有生物中性/生物相容的涂层。
本发明的另一方面涉及本发明的金属纳米颗粒作为诊断剂的用途,更具体而言涉及在超声中(例如靶向超声造影成像)作为超声造影剂的用途。这样,本发明涉及具有一种或多种上述特征的金属纳米颗粒在制备造影剂中的用途,用于超声造影成像。这包括了金属纳米颗粒用于组织或部分组织可视化的用途,以及金属纳米颗粒在探测特定靶,例如,但不限于,细胞标记、病原体等中的用途。
此外,根据本发明的一个特定方面,所述金属纳米颗粒也可以使用能将本发明的颗粒用于组合成像技术的其他成像工具进行探测。
本发明的另一方面是诊断方法,包括将根据本发明的造影剂施用到动物或者人类患者,并对动物或者人实施超声成像检查。或者,根据本发明的另一方面,将造影剂施用到动物或人类组织,以进行离体诊断。
本发明涉及金属纳米颗粒在超声造影剂中的用途并涉及超声造影剂的制备和设计。
根据本发明的金属纳米颗粒具有1-100nm、优选低于50nm、更具体地是30nm或更低的直径。在本发明中,颗粒的形状被认为不是关键的或者非限制性的。可采用任何规则(例如球形、多边形等)或者不规则形状。类似地,在本发明中,粒度分布也被认为不是关键的或者限制性的,尽管在某些应用中一定的尺寸范围可能是有利的。已经记载有用于制备纳米颗粒的不同方法,包括溶液中的成核作用(即化学合成)和蒸汽冷凝或火焰或者喷雾技术(Gutsch等人,2002年,KONA20:24-34;Axelbaum,2001,Powder Metall.43(3):323-325),还有更近来描述的激光烧蚀、在流动液体上真空蒸发(VERL)和化学气相沉积(CVD)技术也是合适的。附加或者可供替换地,合适尺寸的纳米微粒分布可以通过过滤获得。可以采用任何将固体研磨成可用于本发明的颗粒粒度的常规方法。根据一个实施方案,制备方法得到非聚集或者非成簇的金属纳米颗粒。
本发明的金属纳米颗粒的一个重要特征是它们的声阻抗,这使得它们适合用作超声剂。声阻抗(Z)被定义为在介质中密度(ρ)和声速(c)的乘积(Kinsler等人,1982、Fundamentals of acoustics,第3版,John Wiley and sons,New York)。本发明的金属纳米颗粒的声阻抗应当显著高于身体组织的声阻抗,大部分身体组织的声阻抗为1.3-1.7×105g/cm2s(平均值为1.58×105g/cm2s)。本发明提供了根据本发明的金属纳米颗粒,其具有至少35×105g/cm2s、更具体地为至少50×105g/cm2s的声阻抗。最大声阻抗不是本发明的限制因素,但是据设想为约120×105g/cm2s。
具有适于本发明范围的声阻抗的金属的实例是金、银、铂、钯、钨或钽、铼或者它们的混合物、或者金属的合金,例如铂和铱。用于金属纳米颗粒的金属优选是化学稳定和无毒的金属或者可以通过合适的涂层变得化学稳定。在这方面特别有前景的是结合了合适的声阻抗和稳定性以及有限毒性特征的金属。根据一个实施方案,该金属是贵金属。根据本发明的一个具体方面,所述金属是非磁性的。
根据一个具体实施方案,本发明的金属颗粒是基本实心的金属颗粒,意味着a)它们的中心不是空心的,和b),除了下述的涂覆层外,它们基本上由一种或多种金属制备,即由实心金属核形成且不与非金属化合物如蛋白质、多糖或者其他结构化合物结合(除了外层之外),即它们是实心金属颗粒。
根据本发明的具体实施方案,所述金属颗粒包括稳定的无毒涂料,从而降低颗粒聚集。该涂层优选是生物中性和/或生物相容的。适合该目的的涂层在现有技术中已有记载并包括天然和合成碳水化合物、合成聚氨基酸或者生理学上可容许的合成聚合物(包括适体)及其衍生物。
碳水化合物包括天然和合成的结构多糖例如果胶和果胶片段例如聚半乳糖醛酸、葡糖胺多糖和磺酸脂粘多糖(例如肝素、类肝素、角质素、皮肤素、软骨素和透明质酸)、葡聚糖、纤维素和海洋多糖例如藻酸盐、角叉菜胶和壳聚糖和它们的衍生物。
可以用作涂料的合成聚合物包括但不限于聚氨基酸、聚丙烯酸酯和聚苯乙烯。在聚氨基酸中,赖氨酸、谷氨酸和门冬氨酸和它们的酯(例如甲酯和乙酯)的均聚物和共聚物是所设想的涂料的非限制性实例。此外,还设想了具有多嵌段共聚物的涂料,例如多嵌段的聚乳酸(PLA)、聚羟乙酸(PGA)、聚酐、聚磷嗪或者聚己内酯(PCL)。根据一个具体实施方案,金属纳米颗粒可以配备不同涂层的组合。
可替换地,所述金属颗粒可以用稳定的薄氧化物层进行涂覆,前提是该层是无毒的。这种涂层给颗粒带来电荷,导致颗粒间的电排斥。但是,这种涂层特别适合将金属纳米颗粒用于低离子浓度组织中,因为离子会降低电子排斥,导致颗粒的附聚(例如在血液中)。
根据本发明的涂层剂可以含有反应性官能团例如胺、活性酯、醇和羧酸根。这种官能团可以被粘附到生物活性分子、尤其是生物靶向特异性试剂的颗粒表面。合适的生物靶向特异性试剂可以是细胞、微生物例如寄生物如线虫或者细菌、器官或者组织特异性分子例如肽或者蛋白质,或者抗体或其片段。术语生物靶向特异性试剂包括针对特异性外来试剂和/或毒剂的分子或者官能团。所述涂料也可能包括影响颗粒的电荷、亲油性或亲水性或该颗粒进入细胞膜的能力的分子。
本发明的一个具体实施方案涉及被靶向到具体器官或组织的金属纳米颗粒。这可以通过将组织或者器官-特异性分子连接到纳米颗粒的表面而实现。这种分子之一是针对器官或者组织的特异性抗原的抗体。例如,这种抗体可能是对与肿瘤有关的抗原或抗肌凝蛋白抗体有特异性的多克隆的或者单克隆的抗体。可以用于结合的多克隆或者单克隆抗体的非限制性实例特别包括那些主要针对在细胞膜中存在的抗原。例如,适合用于肿瘤可视化的是多克隆或单克隆的抗体本身和/或它们的片段(Fab、F(ab)2),其例如针对癌胚胎抗原(CEA)、人类绒毛膜促性腺激素(β-hCG)或者其他在肿瘤中存在的抗原例如糖蛋白。抗肌凝蛋白抗体、抗胰岛素和抗纤维蛋白抗体和/或片段也是特别合适的。可替换地,所述分子是用于具有组织特异性表达模式的受体的配体。在本发明的范围内,术语“细胞标记”是指任何能识别特异性细胞、细胞类型、组织、组织类型、器官或者器官类型的分子。
本发明的另一具体实施方案涉及用药物涂覆的颗粒或者具有引入到涂层中的药物的颗粒,用作药物递送试剂或者用于诊断和治疗结合用途。治疗剂可以从宽范围的药物中选择并由治疗靶决定。
任选地,所述颗粒进一步用这样的材料涂覆,该材料向颗粒提供亲水性涂层以使血液组分的摄取量最小和/或提供颗粒-细胞相互作用的空间阻隔,以使肝的摄取量最小化。这种材料的实例是称为tetronic908的嵌段共聚物(US 4904497)。
所述造影剂可以用于所有在治疗和诊断中的声波应用,例如多普勒频移或者B模式超声波检查法。如在US 6165440中所述,超声波可以用于获得肿瘤血管的穿孔、间质中的微对流和/或癌细胞膜的穿孔。依据这一原则,本发明的经涂覆的纳米颗粒可以用于实现大分子治疗剂进入癌细胞中的强化递送,而对普通组织仅有最小的热和机械损害。
本发明的颗粒任选地被配制到用于肠道或者肠胃外施用的诊断组合物中。例如肠胃外配制剂有利地包括根据本发明的经涂覆金属颗粒的无菌水溶液或者悬浮液。在现有技术中已知各种用于制备合适的药物溶液和悬浮液的技术。这种溶液还包括药物可接受缓冲液和任选的添加剂,例如但不限于电解质(例如氯化钠)或者抗氧化剂。肠胃外的组合物可以直接注射或者与植物制剂(例如甲基纤维素、乳糖、甘露醇)和/或表面活性剂(例如卵磷脂、Tweens.RTM.,Myrj.RTM.)中的一种或多种常规辅助剂混合。
常规赋形剂是药物可接受的适合肠胃外、肠道或者局部施用的有机或者无机载体物质,其不与这些试剂进行有害的反应。合适的药物可接受辅助剂包括但不限于水、盐溶液、醇、阿拉伯胶、植物油、聚乙二醇、明胶、乳糖、直链淀粉、硬脂酸镁、滑石粉、硅酸、粘性石蜡、香料油、脂肪酸甘油一酯和脂肪酸甘油二酯、季戊四醇脂肪酸酯、羟基甲基纤维素、聚乙烯基吡咯烷酮等。药物制剂可以经灭菌和视需要与辅助剂例如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂、香味剂和/或芳香物质等不会与活性化合物起有害反应的物质混合。
如本领域所公知的,用于肠道施用的配制剂可以大幅度变化。通常,这种配制剂包括在含水溶液或悬浮液中的诊断有效量的金属颗粒。可以使用其中采用了甜味载体的糖浆、酏剂等。可替换地,该配制剂可以作成具有滑石粉和/或碳水化合物载体或粘合剂等的片剂、锭剂、栓剂或胶囊中,该载体优选为乳糖和/或玉米淀粉和/或土豆淀粉。
对于肠胃外的应用,特别合适的是可注射的灭菌溶液,优选油或水溶液,以及悬浮液、乳液或者植入物(包括栓剂)。安瓿是方便的单位剂量。所述含有金属纳米颗粒的造影剂优选用于肠胃外应用,例如作为可注射溶液。
本发明的诊断性组合物以常规方式用于超声程序中。该诊断组合物以足以提供足够可视化的量全身性或者局部施用到温血动物待成像的器官或组织,随后该动物经受医学诊断程序。这种剂量可能在宽范围内变动,取决于所采用的诊断技术和待成像的器官。
本发明的造影剂通常含有每升1微摩尔-1摩尔、优选0.1-100毫摩尔的金属,和通常以每千克体重0.001-100毫摩尔、优选0.1-10毫摩尔金属的量服用。这些造影剂经肠道或者肠胃外地施用到哺乳动物包括人类中。通常,诊断测试在施用后约5-30分钟后开始。
根据本发明的一个具体实施方案,本发明的诊断组合物用于成像,即在离体组织样品或者器官中进行组织结构或者靶分子的可视化,即在已经完全或者部分与动物或者人体分离的组织样品或者器官上。
设想了本发明的造影剂在许多应用中的用途,包括所有本领域中已有记载的造影剂应用,例如但不限于组织、部分组织或者其中结构(例如作为示踪剂)的可视化和诊断。例如,造影剂用于心血管系统的可视化(例如室壁运动分析、心肌灌注、辨识心肌膜中的梗塞或缺血区域、辨识血凝块)或者肝的可视化(肝功能、检测肝肿瘤)。所设想的造影剂的其他用途包括,但不限于,肠胃道的可视化、肿瘤的可视化、辨识睾丸和卵巢扭转、评价肾和其它移植的器官、远程测量温度、生理压力和造影剂引导和控制的局部药物递送。
根据一个方面,本发明的诊断组合物用于与不同成像方法结合。这样,取决于它们的特性,本发明的纳米颗粒可能适用于X射线分析。这样,本发明的一个具体实施方案涉及用于组合成像方法的诊断组合物。
如在本文中使用,“包括”应理解为明确了存在所提及的特征、整体、步骤或者组分,但并不排除存在或加入一个或多个特征、整数、步骤或组分或它们的组合。在本文中“一(a)”或者“一(an)”并不排除复数的情况。
下面的实施例可以结合附图进行理解,所述实施例并非意图将本发明限制到具体的实施方案中,而附图在此引入作为参考,其中:
图1:用于反射增强(不可压缩层)的理论模型的参数的图解。
图2:在具有与人体组织平均声学特性相同的材料上,50nm Au层相对于250nm液体全氟化碳层(PFO)的理论计算的反射增强,其作为频率的函数。
图4:2μm PC箔和带50nm蒸发Au的2μm PC箔的积分反射强度(峰面积),它们作为增益的函数。
图5:作为增益(由换能器产生的强度(dB))的函数的积分反射强度(峰面积)。
实施例
实施例1-金箔对全氟化碳乳液液滴的反射增强的理论计算
层的反射增强可以使用数学模型进行计算:
其中:
‘r(k)’是不可压缩材料的振幅反射系数,
‘t’是介质1(例如水)介质2(超声造影层/剂)和介质3(例如基材)之间的复合透射系数,
‘r’是介质1(例如水)介质2(超声造影层/剂)和介质3(例如基材)(参见图1)之间的复合反射系数,
‘k’是超声波在造影层中的波数,
‘d’是造影层的厚度。
和增强为20·log(|r(k)|/|r0|)
‘r(k)’是不可压缩材料的振幅反射系数,r0是不含造影剂的基材表面的振幅反射系数。
经计算的250nm的全氟化碳乳液液滴层的增强与在具有脾组织的声学性质的材料(1.6×105g/cms)上的这种颗粒层上观察到的超声反射增强相一致,脾组织的声阻抗非常接近与人类组织的平均声阻抗(1.58×105g/cms)。
图2显示了在人类衣服上的50nm Au层对比250nm液体全氟化碳、脂质包封的纳米颗粒乳液层(PFO)的理论计算反射增强,其作为频率的函数。
可以总结得出,50nm Au层的反射增强高于由250nm液体全氟化碳、脂质包封的纳米颗粒乳液层得到的反射增强。
实施例2-作为频率函数的50nm铂层、50nm钨层、50nm金层和50nm
钽层的理论预测反射增强。
图3显示了作为频率函数的50nm铂层、50nm钨层、50nm金层和50nm钽层的理论预测反射增强。
实施例3-50nm金层的反射增强测定
将50nm金蒸发到2微米的聚碳酸酯(PC)箔上。配备了22MHz换能器的Taberna Pro Medicum数字超声成像系统用于测定具有和不具有蒸发金层的PC箔的反射。2μm PC箔和具有50nm蒸发Au的2μm PC箔的积分反射强度(峰面积)作为增益的函数显示在图4中。
在2微米聚碳酸酯箔上的50nm蒸发的金获得了4dB的反射增强。
实施例4-银纳米颗粒层的反射增强测量
用50nm的银颗粒层涂覆2微米的聚碳酸酯(PC)箔,所述颗粒具有30nm的尺寸。配备了22MHz换能器的Taberna Pro Medicum数字超声成像系统用于测定具有和不具有Ag层的PC箔的反射性。结果示于图5。
可以总结出,50nm的银纳米颗粒层将PC箔的反射率增加2.5倍。因此,金属纳米颗粒薄膜提供了显著的增强,显示了这些颗粒作为超声反射体的实用性。
Claims (13)
1.具有大于35·105g/cm2s的声阻抗的实心金属纳米颗粒在制备超声造影剂的用途。
2.权利要求1的用途,其中所述实心金属纳米颗粒具有大于50·105g/cm2s的声阻抗。
3.权利要求1和2任一项的用途,其中所述金属纳米颗粒具有1nm-100nm的直径。
4.权利要求1和2任一项的用途,其中所述金属纳米颗粒具有1nm-50nm的直径。
5.权利要求1和2任一项的用途,其中所述金属是非磁性的。
6.权利要求1和2任一项的用途,其中所述金属选自金、银、铂、钯、钨或者钽、铼或它们的混合物。
7.权利要求1和2任一项的用途,其中所述金属是贵金属。
8.权利要求1和2任一项的用途,其中所述实心金属纳米颗粒包括一种或多种涂层。
9.权利要求8的用途,其中所述一种或多种涂层包括天然或者合成的碳水化合物、合成的聚氨基酸或者生理学上容许的合成聚合物或者它们的衍生物。
10.权利要求8的用途,其中所述一种或多种涂层包括治疗剂。
11.权利要求1和2任一项的用途,其中所述实心金属纳米颗粒包含附着到所述金属颗粒的表面上的一种或多种生物靶向特异性分子。
12.权利要求11的用途,其中所述生物靶向特异性分子辨认出靶,所述靶选自细胞标记、病原体和外来试剂和/或毒剂。
13.权利要求11的用途,其中所述生物靶向特异性分子是抗体或其片段。
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NO20052429D0 (no) * | 2005-05-20 | 2005-05-20 | Amersham Health As | Konstrastmidler |
US9149545B2 (en) | 2005-11-02 | 2015-10-06 | General Electric Company | Nanoparticle-based imaging agents for X-ray/computed tomography and methods for making same |
WO2008101019A2 (en) * | 2007-02-13 | 2008-08-21 | Board Of Regents, The University Of Texas System | Molecular specific photoacoustic imaging |
EP2318086B1 (en) * | 2008-07-23 | 2016-04-13 | Koninklijke Philips N.V. | Ultrasound mediated drug delivery |
WO2011097824A1 (zh) * | 2010-02-12 | 2011-08-18 | 大连科林爱纳米科技有限公司 | X射线或者ct造影剂用金纳米粒子的制造方法 |
RU2444296C2 (ru) * | 2010-03-24 | 2012-03-10 | Государственное образовательное учреждение высшего профессионального образования "Уральская государственная медицинская академия Федерального агентства по здравоохранению и социальному развитию" (ГОУ ВПО УГМА Росздрава) | Способ использования суспензий наночастиц оксидов металлов в качестве контрастных веществ для ультразвуковой визуализации сердца и сосудов |
CN103083687B (zh) * | 2013-01-16 | 2016-04-13 | 东南大学 | 一种银、铂纳米簇在肿瘤靶向成像的应用 |
CN103100093B (zh) * | 2013-01-23 | 2015-05-06 | 中山大学附属第三医院 | 一种负载小干扰rna的纳米级脂质微泡超声造影剂及制备方法 |
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