CN113058044A - 一种动态有机钆纳米颗粒及其应用 - Google Patents

一种动态有机钆纳米颗粒及其应用 Download PDF

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CN113058044A
CN113058044A CN202110327892.6A CN202110327892A CN113058044A CN 113058044 A CN113058044 A CN 113058044A CN 202110327892 A CN202110327892 A CN 202110327892A CN 113058044 A CN113058044 A CN 113058044A
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aqueous solution
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陈世桢
孙献平
周欣
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Wuhan Zhongke Polarized Medical Technology Co ltd
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Abstract

本发明公开了一种动态有机钆纳米颗粒及其应用，该纳米颗粒由以下方法制备而成：1、分别配制100μM的钆前体水溶液和4mM的三(2‑羧乙基)膦水溶液；2、将钆前体水溶液和三(2‑羧乙基)膦水溶液混合，钆前体和三(2‑羧乙基)膦的摩尔比为25:1，在室温下搅拌，得到钆中间体；3、将钆中间体用Na2CO3水溶液调节pH值至6.0，在室温下搅拌，得到所述的动态有机钆纳米颗粒。该纳米颗粒的粒径在其自组装的不同阶段，其粒径可动态变化，可在其自组装的不同阶段分别作为T1造影剂和T2造影剂，同一造影剂即可实现MRI信号正增强和负增强效果，可有效提高检测的准确性。

Description

一种动态有机钆纳米颗粒及其应用
技术领域
本发明涉及磁共振成像技术领域，具体涉及一种动态有机钆纳米颗粒及其应用。
背景技术
磁共振成像(MRI)作为一种非侵入性且无放射性的成像技术，长期以来被用作医学诊断的重要影像学工具之一。相比于其他医学影像技术，如计算机断层扫描(CT)，正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)等技术，MRI具有诸多的优势，如对检查对象无损无创，可以获取具有高空间分辨率和软组织对比度的三维图像信息。然而，MRI在医学诊断中存在灵敏度相对较低的缺点，目前主要是通过增强成像对比度来提高MRI的灵敏度。MRI造影剂的应用可以有效增强组织对比度，该领域得到科学家的广泛关注，其作用机制一般是缩短目标部位质子的T1和T2弛豫时间，即质子的自旋-晶格或纵向弛豫时间，及自旋-自旋或横向弛豫时间。T1越短，图像信号越强(正增强)，T2越短，图像信号越弱(负增强)。
MRI造影剂的效率通常用弛豫率r1或r2表示，即能够缩短每毫摩尔造影剂弛豫时间的能力。根据显像特点，通常可将MRI造影剂分为两类：T1造影剂(阳性造影剂)和T2造影剂(阴性造影剂)。T1造影剂的作用主要是缩短纵向弛豫时间T1，从而产生明亮的图像，一般是钆(Gd3+)或锰(Mn2+)等顺磁性化合物，例如钆的螯和物，由于Gd的强顺磁性，该造影剂可明显缩短质子的T1，增强对比度，是临床常用的造影剂。但钆螯合物的临床上的应用也存在一些缺点，如体内循环时间短，从而影响需要较长扫描时间的高分辨率成像；不易对其进行功能化修饰；另外具有诱发肾功能受损患者，尤其是老年患者肾源性系统纤维化(NSF)的风险。T2造影剂主要起到缩短横向弛豫时间T2的作用，从而产生信号减弱的图像，即暗图像。超顺磁性纳米颗粒(通常是氧化铁纳米颗粒)由于具有较高的r2、良好的生物相容性和较长的体内循环时间而被广泛用作T2造影剂，但它在临床上的应用主要受到以下缺点的限制：负造影效果和磁敏感伪影。产生暗信号可能会误导T2加权MRI的临床诊断，因为该信号与出血、钙化或金属沉积的信号混淆，而磁敏感伪影通常会使背景图像失真。由于这些原因，T1造影剂比T2造影剂在精准的高分辨率成像上更具优势。在实际应用中，每种MR机制都具有其信号特征，这些特征既有优势也有劣势，不同程度地影响对比增强MRI的整体效率。
为了克服上述顺磁性螯合物的缺点，近年来基于无机纳米颗粒的T1/T2双模态MRI造影剂得到了广泛的研究，与顺磁性螯合物相比，基于纳米颗粒的造影剂具有很多受益于其纳米结构的优势：1、造影剂的磁性质可根据纳米颗粒的尺寸、性质、组成和组装进行调整；2、纳米颗粒的体内循环时间更长，在临床上的应用更具潜力；3、纳米颗粒的表面易于修饰，可与靶向基团或其他探针结合，从而实现靶向和多模态成像。理论上，T1/T2双模态MRI造影剂可通过T1造影剂和T2造影剂两者的杂合来获得，近年来，已有多种基于无机纳米颗粒的T1/T2双模态MRI造影剂被开发出来，例如超小Fe3O4磁性纳米颗粒(粒径约5nm)有潜力作为T1/T2双模态MRI造影剂。然而，尽管有机纳米颗粒造影剂的功能化修饰更具优势，但目前对其研究仍较少。
在2013年，有研究报道了一种含钆的有机纳米颗粒，其制备是基于具有生物相容性的1,2-氨基硫醇和氰基苯并噻唑(CBT)的缩合反应，该研究证明了基于CBT的含钆小分子可通过缩合反应生成疏水性的低聚物，这些低聚物会进一步自组装形成超分子纳米颗粒，可作为T1造影剂。在相同钆浓度下，这些纳米颗粒比含钆小分子前体表现出增强的纵向弛豫率。然而，含钆纳米颗粒体系作为T2造影剂的研究鲜有报道。由于纳米颗粒的粒径影响弛豫率，不同粒径的含钆纳米颗粒有可能作为T1或T2造影剂，因此含钆纳米颗粒具有成为T1/T2双模态MRI造影剂的潜力，以有效提高MRI的灵敏度。
发明内容
基于上述现有技术，本发明提供了一种动态有机钆纳米颗粒及其应用，该纳米颗粒的粒径在其自组装的不同阶段，其粒径可动态变化，可在其自组装的不同阶段分别作为T1造影剂和T2造影剂，同一造影剂即可实现MRI信号正增强和负增强效果，可有效提高检测的准确性。
实现本发明上述目的所采用的技术方案为：
一种动态有机钆纳米颗粒，由以下方法制备而成：
1、分别配制100μM的钆前体水溶液和4mM的三(2-羧乙基)膦水溶液；
2、将钆前体水溶液和三(2-羧乙基)膦水溶液混合，钆前体和三(2-羧乙基)膦的摩尔比为25:1，在室温下搅拌，得到钆中间体；
3、将钆中间体用Na2CO3水溶液调节pH值至6.0，在室温下搅拌，得到所述的动态有机钆纳米颗粒。
一种动态有机钆纳米颗粒在作为T1/T2双模态磁共振成像造影剂的应用。
与现有技术相比，本发明的优点与有益效果在于：
1、本发明的有机钆纳米颗粒可用于T1/T2双模态MRI造影剂，由于纳米颗粒粒径的动态变化，在其自组装的不同阶段可分别作为T1造影剂和T2造影剂。
2、本发明的有机钆纳米颗粒易于修饰，通过合适的化学修饰方法可赋予其环境响应性或靶向性等功能。
3、本发明的有机钆纳米颗粒作为T1/T2双模态MRI造影剂，在Gd3+浓度为100μM的条件下，当粒径为8nm时可作为T1造影剂，弛豫比r2/r1为2.71；当粒径为10nm时可作为T2造影剂，弛豫比r2/r1为5.80，证明其可作为T1/T2双模态MRI造影剂。
附图说明
图1本实施例1制备的动态有机钆纳米颗粒的合成线路图和合成原理图：图1(a)为合成路线图，图1(b)为合成原理图。
图2为实施例1制备的动态有机钆纳米颗粒在干燥状态下的TEM图。
图3为实施例1制备的Gd-intermediate的MALDI-MS的表征图。
图4为实施例1制备的Gd-nanoparticle的紫外-可见吸收光谱图(调节pH后反应2h时)。
图5为实施例1制备的Gd-nanoparticle在不同时间点对应的紫外-可见吸收光谱图。
图6为实施例1制备的Gd-nanoparticle的动态光散射图(调节pH后反应2h时)。
图7为实施例1制备的Gd-nanoparticle在不同时间点对应的动态光散射图其中图7(a)为0.5h时的动态光散射图，图7(b)为1h时的动态光散射图，图7(c)为1.5h时的动态光散射图，图7(d)为2h时的动态光散射图，图7(e)为2.5h时的动态光散射图，图7(f)为3h时的动态光散射图。
，图8为实施例1制备的Gd-nanoparticle用于造影剂在不同时间点的T1MR加权成像图(a)和T2MR加权成像图(b)。
图9为实施例1制备的Gd-nanoparticle用于造影剂在不同时间点的r1、r2曲线图(a)和弛豫比曲线图(b)。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
1、钆前体的合成：
按照文献(Liang.G L.et a1.Controlled Self-Assembling of GadoliniumNanoparticles as Smart Molecular Magnetic Resonance Imaging ContrastAgents.Angew.Chem.Int.Ed.，50，6283-6286，(2011))公开的方法进行合成；
2、钆中间体的合成：
2.1、分别配制浓度为100μM的Gd-precursor水溶液和4mM的三(2-羧乙基)膦(TCEP)水溶液；
2.2、取1mL 100μM的Gd-precursor水溶液，往其中加入1μL 4mM的TCEP水溶液，在室温下搅拌，得到钆中间体，记为Gd-intermediate；
3、有机钆纳米颗粒的制备：
配制浓度为0.1M的用Na2CO3水溶液，将钆中间体用Na2CO3水溶液调节pH值至6.0，在室温下搅拌，得到所述的动态有机钆纳米颗粒，记为Gd-nanoparticle。
本实施例制备动态有机钆纳米颗粒的合成线路图如图1(a)，其合成原理图如图1(b)所示，从图1(a)和图1(b)可知，本实施例制备的有机钆纳米颗粒是基于具有生物相容性的1,2-氨基硫醇和氰基苯并噻唑(CBT)的缩合反应，其MRI成像功能模块为Gd-DOTA螯合物，含钆小分子在三(2-羧乙基)膦(TCEP)的还原作用下生成1,2-氨基硫醇基团，随后与CBT的氰基发生缩合反应，形成粒径更大、疏水性更强的低聚物Gd-oligomer，再进一步自组装形成有机钆纳米颗粒。在颗粒间疏水作用的驱动下，自组装的纳米颗粒逐渐增大，该体系涉及从小分子到低聚物，再到纳米颗粒的动态过程。
将本实施例1制得的Gd-nanoparticle通过透射电子显微镜(TEM)观察其干燥状态下的粒径，所得的TEM图如图2所示，由图2可以看出，该有机钆纳米颗粒分散性良好，其粒径分布范围为8～23nm，干燥状态下的纳米颗粒粒径明显小于溶液状态中的纳米颗粒粒径，这表明本实施例所得的有机钆纳米颗粒在其水溶液中具有高度溶胀的外层。
将本实施例制备的Gd-intermediate进行基质辅助激光解吸/电离质谱(MALDI-MS)表征，所得的质谱图如图3所示，其分子离子峰为1862.92，证明了含钆小分子Gd-precursor在三(2-羧乙基)膦(TCEP)的还原作用下生成1,2-氨基硫醇基团，随后与CBT的氰基发生缩合反应，该缩合反应生成了二聚体Gd-intermediate。
将本实施例制备的Gd-nanoparticle进行紫外-可见吸收光谱(UV-Vis)分析，所得的紫外-可见吸收光谱如图4所示，由图4可知，当TCEP加至Gd-precursor溶液中后，该混合物在500-700nm范围内没有吸收，调节pH反应2小时后，在UV-Vis光谱中记录到明显的吸收，表明体系中自组装形成了具有共轭电子带的钆低聚物和/或纳米颗粒。在调节pH后反应的整个过程中，500-700nm的吸光度随时间的变化过程如图5所示。
经本实施例制备的Gd-nanoparticle经动态光散射(DLS)分析，调节pH反应2小时测得的DLS结果如图6所示，由图6可知，该有机钆纳米颗粒的水合粒径范围在18～55nm之间。本实施例的Gd-nanoparticle在调节pH后不同时间点测得的DLS结果如图7所示，从图7可以看出，随着时间的增加，水合粒径在不断增大。
试验一、本发明的动态有机钆纳米颗粒Gd-nanoparticle用于造影剂的磁共振成像实验试验方法：
利用400MHzNMR谱仪对有机钆纳米颗粒Gd-nanoparticle以0.5小时为时间间隔进行T1-加权/T2-加权的核磁共振体外水管成像，得到有机钆纳米颗粒Gd-nanoparticle以0.5小时为时间间隔的纵向弛豫速率r1和横向弛豫速率r2仪器测试参数：matrices＝64×64，FOV 3.00cm，slice thickness＝1.0mm，，同时用透射电子显微镜(TEM)观察有机钆纳米颗粒Gd-nanoparticle在干燥状态下的粒径；
试验结果：
所得的磁共振成像结果如表1和图8所示：
表1
Figure BDA0002995299630000061
将表1的数据进行作图，所得的r1曲线图和r2曲线图如图9(a)所示，由表1、图8和9(a)可知，实施例制备的动态有机钆纳米颗粒的纵向弛豫时间T1随时间单调减小，而横向弛豫时间T2表现出非单调时间依赖性，即先降低，在一定时间后再增加，具体表现为：纵向弛豫率初始为3.4mM-1s-1，6小时后，逐渐降低为2.1mM-1s-1；同时，其横向弛豫率初始为9.2mM- 1s-1，2小时后增至15.3mM-1s-1，6小时后降至5.6mM-1s-1。
对实施例1制备的有机钆纳米颗粒随时间变化的弛豫比r2/r1作图分析，如图9b所示，弛豫比r2/r1在开始的2小时内从2.71增至5.80，接下来的4小时后降至2.62，这对应于有机钆纳米颗粒的粒径从8nm增至23nm。
实施例1的动态有机钆纳米颗粒的纵向弛豫率逐渐降低归，因于与Gd3+结合的水分子数量随纳米颗粒粒径的增大而减少，因此，实施例1的动态有机钆纳米颗粒作为T1造影剂的最佳粒径为8nm。实施例1的动态有机钆纳米颗粒粒径的增大导致r1的降低和r2的先增大后减小，因此，实施例1的动态有机钆纳米颗粒粒径的轻微增加会引起弛豫比r2/r1的明显提高，2小时后，有机钆纳米颗粒的粒径达到约10nm，弛豫比r2/r1达到最大值5.80，基于此现象，可推断出实施例1的动态有机钆纳米颗粒作为T2造影剂的最佳粒径为10nm。

Claims (2)

1.一种动态有机钆纳米颗粒，其特征在于由以下方法制备而成：
1.1、分别配制100μM的钆前体水溶液和4mM的三(2-羧乙基)膦水溶液；
1.2、将钆前体水溶液和三(2-羧乙基)膦水溶液混合，钆前体和三(2-羧乙基)膦的摩尔比为25:1，在室温下搅拌，得到钆中间体；
1.3、将钆中间体用Na2CO3水溶液调节pH值至6.0，在室温下搅拌，得到所述的动态有机钆纳米颗粒。
2.一种权利要求1所述的动态有机钆纳米颗粒在作为T1/T2双模态磁共振成像造影剂的应用。
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CHUN-YAN CAO等: "Controlled intracellular self-assembly of gadolinium nanoparticles as smart molecular MR contrast agents", 《SCIENTIFIC REPORTS》 *
GAOLIN LIANG等: "Controlled Self-Assembling of Gadolinium Nanoparticles as "Smart" Molecular Magnetic Resonance Imaging Contrast Agents", 《ANGEW CHEM INT ED ENGL.》 *
ZIJUAN HAI等: "γ‑Glutamyltranspeptidase-Triggered Intracellular Gadolinium Nanoparticle Formation Enhances the T2‑Weighted MR Contrast of Tumor", 《NANO LETT.》 *

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