CN110256337A - 一种基于锰的两性羧酸金属有机骨架及其合成方法和应用 - Google Patents
一种基于锰的两性羧酸金属有机骨架及其合成方法和应用 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明公开了一种基于锰的两性羧酸金属有机骨架及其合成方法和应用，该两性羧酸金属有机骨架的重复单元为[Mn2(Cdcbp)2(H2O)4]·3(H2O)。本发明的基于锰的两性羧酸金属有机骨架水稳定性好，细胞毒性低，生物组织相容性高，纵向弛豫率高，具有良好的体外和体内造影性能，可作为一种优秀的磁共振成像造影剂应用于磁共振成像中。而且本发明合成方法原料来源广泛，容易获得，反应条件温和，时间短，可在水溶液中结晶获得，无毒无害，无需惰性气体保护。
Description
技术领域
本发明涉及配位化学领域和影像学领域，具体涉及金属有机骨架、合成方法及其在磁共振成像中的应用。
背景技术
磁共振成像(Magnetic Resonance Imaging,MRI)是核磁共振技术在生物医学上的一个重要应用，具有无辐射性损伤，分辨率高以及成像速度快等优点，可有效检测组织坏死、局部缺血和各种恶性病变((如肿瘤)。虽然磁共振成像技术的发展时间不长，但已经成为现今医学成像技术中不可或缺的一部分，并且极大地推动了医学、神经生理学和认知神经科学的迅速发展。
在临床实施MRI扫描时，正常组织和病变组织有时候仅表现出很小的信号差异，因此大约有35％的临床MRI扫描需要采用磁共振成像造影剂(MRI contrast agents)来增强图像的对比度和分辨率。MRI造影剂可使局部信号强度(SI)与其它部位的SI相比有可观测的变化，达到更好的暴露病变组织的目的。随着造影剂增强MRI成像技术的发展与普及，其成像优势得到越来越多的肯定，加之在分子成像领域的应用潜力，对造影剂性能改善的研究工作也受到越来越多的关注。现在临床最常用的造影剂是含Gd3+的顺磁性金属配位化合物，其中二乙基三胺五乙酸合钆(钆喷酸葡胺，Gd-DTPA)用的最多。然而目前应用的小分子造影剂存在较多问题，如弛豫度低、用量大、毒性高、在血液中循环时间短等，造影效果并不明显。
金属有机骨架(Metal Organic Frameworks,MOFs)是一类由金属中心和有机配体通过自组装的方式，形成的一种多孔晶态材料，具有合成方法简单、成本低廉、物理化学性能独特的特点。因此，该材料在气体的吸附与分离、有机反应催化、生物成像、磁性材料、小分子探针和载药等领域均具有一定的应用前景。但MOFs在MRI造影剂方面的研究却一直未能得到深入。
2006年，美国Lin课题组首次将对苯二甲酸和Gd3+构筑的MOF应用于磁共振成像中，虽然该材料在体外表现出了较高的纵向弛豫率和T1加权成像效果，但由于材料的水稳定性差导致Gd3+容易游离浸出，具有肾源性系统性纤维化的风险，因此无法进行深入的研究。2008年，该课题组选择了毒性较低的Mn2+与对苯二甲酸或均苯三甲酸构筑了两个MOFs作为MRI造影剂，但不幸的是，它们在水中也不稳定，这导致了锰离子的大量泄漏。因此，设计合成具有良好水稳定性的MOFs，对其在MRI造影剂方面的深入研究具有非常重要的意义。
发明内容
针对现有技术的不足，本发明旨在提供一种基于锰的两性羧酸金属有机骨架及其合成方法和应用，合成得到的两性羧酸金属有机骨架的水稳定性好，细胞毒性低，生物组织相容性高，纵向弛豫率高，具有良好的体外和体内造影性能，可作为一种优秀的磁共振成像造影剂应用于磁共振成像中。
为了实现上述目的，本发明采用如下技术方案：
一种基于锰的两性羧酸金属有机骨架，其重复单元为[Mn2(Cdcbp)2(H2O)4]·3(H2O)。
本发明还提供上述基于锰的两性羧酸金属有机骨架的合成方法，包括如下步骤：
S1、将H3CdcbpBr溶解分散在水中，用NaOH溶液将pH调至6.0～7.0，得到配体溶液；
S2、将与H3CdcbpBr等摩尔量的MnCl2溶解于水中，得到锰盐溶液；
S3、将步骤S1中得到的配体溶液和步骤S2中得到的锰盐溶液混合，过滤，滤液置于厚壁耐压瓶后转移到可编程的烘箱；烘箱的温度在4小时内从25℃平稳地升高到100℃，在100℃保持72小时，然后在48小时内冷却到室温，得到无色晶体；
S4、过滤得到所述无色晶体，用甲醇洗涤并真空干燥，得到基于锰的两性羧酸金属有机骨架。
进一步地，所述H3CdcbpBr为N-(3,5-二羧酸苄基)-(3-羧酸)溴化吡啶，分子结构如下所示：
上述基于锰的两性羧酸金属有机骨架可应用于磁共振成像造影剂。
本发明的有益效果在于：
1、本发明的基于锰的两性羧酸金属有机骨架水稳定性好，细胞毒性低，生物组织相容性高，纵向弛豫率高，具有良好的体外和体内造影性能，可作为一种优秀的磁共振成像造影剂应用于磁共振成像中。
2、本发明合成方法原料来源广泛，容易获得；
3、本发明合成方法的反应条件温和，时间短，可在水溶液中结晶获得，无毒无害，无需惰性气体保护。
附图说明
图1为本发明实施例中的基于锰的两性羧酸金属有机骨架中Mn(1)配位环境及其二维结构示意图。省略氢原子和溶剂化物。
图2为本发明实施例中的基于锰的两性羧酸金属有机骨架中Mn(2)配位环境及其二维结构示意图。省略氢原子和溶剂化物。
图3为本发明实施例中基于锰的两性羧酸金属有机骨架的X射线单晶粉末衍射图，显示基于锰的两性羧酸金属有机骨架在浸入大鼠血清、H2O、DMEM以及PBS中10天后的图谱与模拟的、合成的之间的一致性；
图4为本发明实施例中不同浓度的基于锰的两性羧酸金属有机骨架和Gd-DTPA的T1加权MRI(图(a))和1/T1图(图(b))；
图5为本发明实施例中HEK 293细胞加入不同浓度基于锰的两性羧酸金属有机骨架及Gd-DTPA培养72h后的存活率示意图；
图6为本发明实施例中静脉注射基于锰的两性羧酸金属有机骨架后肾脏和肝脏的冠状(上)和轴向(下)动态增强MRI(图(a))及其相应的MRI信号强度(图(b))示意图；
图7为本发明实施例中空白组和基于锰的两性羧酸金属有机骨架组(100μL，500μM)昆明小鼠在给药7天后不同组织的组织形态切片(100×)示意图。
具体实施方式
以下将结合附图对本发明作进一步的描述，需要说明的是，本实施例以本技术方案为前提，给出了详细的实施方式和具体的操作过程，但本发明的保护范围并不限于本实施例。
实施例1
本实施例提供一种基于锰的两性羧酸金属有机骨架的合成方法，包括如下步骤：
S1、将H3CdcbpBr溶解分散在水中，用NaOH溶液将pH调至6.0～7.0，得到配体溶液；
S2、将与H3CdcbpBr等摩尔量的MnCl2溶解于水中，得到锰盐溶液；
S3、将步骤S1中得到的配体溶液和步骤S2中得到的锰盐溶液混合，过滤，滤液置于厚壁耐压瓶(欣维尔)后转移到可编程的烘箱；烘箱的温度在4小时内从25℃平稳地升高到100℃，在100℃保持72小时，然后在48小时内冷却到室温，得到无色晶体；
S4、过滤得到所述无色晶体，用甲醇洗涤并真空干燥，得到基于锰的两性羧酸金属有机骨架。
所述H3CdcbpBr为N-(3,5-二羧酸苄基)-(3-羧酸)溴化吡啶，分子结构如下所示：
实施例2
本实施例旨在对实施例1的合成方法制备得到的基于锰的两性羧酸金属有机骨架进行鉴定。
通过下述元素分析、IR光谱和X-射线单晶衍射分析鉴定，上述实施例1所得到的无色晶体为本发明所述的基于锰的两性羧酸金属有机骨架，其重复单元的分子式为[Mn2(Cdcbp)2(H2O)4]·3(H2O)。
1、元素分析C30H32Mn2N2O19：
理论值：C,43.18；H,3.87；N,3.36；实验值：C,43.27；H,3.22；N,3.29。
2、红外光谱(KBr disk，cm-1)：
3243(s),2925(s),3014(s),1653(m),1599(s),1545(s),1386(s),772(m),695(s)。
3、X-射线单晶衍射：
晶体学参数和部分键长如表1和表2所示。
表1[Mn2(Cdcbp)2(H2O)4]·3(H2O)的晶体学参数
aR＝||Fo|-|Fc|/|Fo|.bwR＝{w(Fo 2-Fc 2)2/w(Fo 2)2}1/2.cGOF＝{w((Fo 2-Fc 2)2)/(n-p)}1/2
表2[Mn2(Cdcbp)2(H2O)4]·3(H2O)的部分键长键角
Symmetry transformations used to generate equivalent atoms:#1-x+2,-y+2,-z-1；#2x-1,y,z；#3-x+1,-y+1,-z；#4x+1,y,z.
X-射线单晶衍射结果表明，所述基于锰的两性羧酸金属有机骨架属于三斜晶系，空间群为P-1，每个不对称单元中含有一个[Mn2(Cdcbp)2(H2O)4]分子和三个游离水分子。
如图1-2所示，每个Mn中心由两个水分子的O原子和三个Cdcbp配体上三个羧酸基团的四个O原子配位，其中两个羧酸处于单齿配位模式，第三个羧酸处于螯合配位模式，从而形成略微扭曲的八面体配位几何形状。
如图1所示，每对Mn(1)离子由Cdcbp配体上的一对苯甲酸盐以μ3-COO(η1:η2)模式连接，并且每个Mn(1)离子以单齿配位模式进一步配位一个吡啶基羧酸盐和两个水分子的O原子，从而形成[Mn(1)2(Cdcbp)4(H2O)4]单元。这样的单元可以通过三个等效单元进一步延伸，从而沿a轴方向形成一维(1D)链(图2)。此外，每对Mn(2)离子通过一对μ2–COO(η1:η1)基团连接，并且每个Mn(2)离子进一步跟一个螯合羧酸盐和两个水分子中的O原子配位，从而形成[Mn(2)2(Cdcbp)4(H2O)4]单元。这样的单元也通过三个等效单元进一步延伸，从而沿a轴方向形成一维(1D)链。最后，在b方向上，由[Mn(1)2(Cdcbp)4(H2O)4]单元和[Mn(2)2(Cdcbp)4(H2O)4]单元形成的两条1D链通过羧酸盐连接，从而形成二维(2D)结构。
实施例3
本实施例采用实施例1得到的基于锰的两性羧酸金属有机骨架作为MRI造影剂进行性能研究。具体研究方法如下所述：
1、常温下，实施例1合成得到的基于锰的两性羧酸金属有机骨架的水溶液浓度为621μM。为了研究基于锰的两性羧酸金属有机骨架的水稳定性，将基于锰的两性羧酸金属有机骨架的粉末分别浸泡在大鼠血清、H2O、DMEM培养基(10％FBS，1％PS)以及PBS缓冲液(1X，pH＝7.4)中，10天后用德国Bruker APEX II X射线单晶粉末衍射仪对这些粉末进行表征。
2、体外造影性能测试：在室温条件下，以Gd-DTPA为对照，用去离子水将基于锰的两性羧酸金属有机骨架和Gd-DTPA分别配成浓度为31.25、62.5、125、250和500μM的溶液。利用北京斯派克SPEC-RC2核磁共振成像系统在0.5T的磁场强度下测量基于锰的两性羧酸金属有机骨架在不同浓度下的纵向驰豫时间(T1)并记录基于锰的两性羧酸金属有机骨架的T1加权成像效果。以1/T1为纵坐标，基于锰的两性羧酸金属有机骨架浓度为横坐标作图，线性拟合得出基于锰的两性羧酸金属有机骨架的弛豫率r1。
3、体外细胞毒性研究：将人类胚胎肾细胞HEK 293均匀分散在DMEM培养基中(含10％胎牛血清，100mg/mL链霉素和100U/mL青霉素)，温度为37℃，CO2浓度为5％的潮湿环境下培养24h。离心弃去旧培养基，用新鲜培养基使细胞重新悬浮并以3×104个细胞/孔的密度接种于96孔板中。然后，用含有各种浓度的基于锰的两性羧酸金属有机骨架和Gd-DTPA的新鲜DMEM代替旧培养基，孵育72h，然后每孔加入0.5mg/mL的MTT溶液10μL，继续孵育4小时。加入DMSO(150μL/孔)溶解甲臢，停止反应。用酶标仪在波长490nm处测定每孔溶液的吸光度(OD)，每个实验进行三次。用以下公式计算细胞存活率：
细胞存活率(％)＝[(OD1-OD3)/(OD2-OD3)]×100
其中OD1为细胞中加入基于锰的两性羧酸金属有机骨架的吸光度；OD2为细胞中未加入基于锰的两性羧酸金属有机骨架的吸光度；OD3为培养基的吸光度。
4、体内造影性能研究：使用BALB/c小鼠(6-8周，18±2g，n＝3)进行测试，用戊巴比妥钠麻醉(1％，100μL)，尾端静脉注射基于锰的两性羧酸金属有机骨架(200μL，2.4mg/kg小鼠体重)，用3.0T小型动物MRI扫描仪，磁孔尺寸为310mm，最大梯度振幅为600mT/m，最大压摆率为2500T/m/s。
5、体内毒性研究：在雄性昆明小鼠(20-22g)上评估体内毒性。小鼠在12小时光照/黑暗循环下生活在空调动物房中，并用商业饮食和自来水喂养。所有动物程序均遵照机构伦理委员会关于动物福利的规定和指南进行。将小鼠随机分为2组，每组3只，包括一个空白组和一个基于锰的两性羧酸金属有机骨架组。静脉注射浓度为500μM的基于锰的两性羧酸金属有机骨架(100μL)进入实验组小鼠的尾静脉。一周后，处死动物并解剖出心脏，肝脏和肾脏，用苏木精-伊红染色并在光学显微镜下检查。
实验结果：
如图3所示，X-射线粉末衍射结果表明，实施例1合成得到的基于锰的两性羧酸金属有机骨架浸泡在大鼠血清、H2O、DMEM以及PBS中10天，其骨架结构并未发生明显的变化，说明化合物对水具有很高的稳定性。体外造影结果(图4)显示，化合物的纵向弛豫率(r1)为32.73mM-1·S-1，是对照组Gd-DTPA(r1＝4.85mM-1·S-1)的6.7倍，显示出更明显的T1加权成像效果。体外MTT实验(图5)表明化合物具有良好的生物相容性和对模型细胞系较低的细胞毒性。在体内MRI(图6)中，两个肾在5分钟后显示出显著的T1加权阳性信号增强。强信号持续时间超过4小时，在24小时后衰减。此外，肝脏的信号强度也随着肾脏的增强而增加。体内毒性实验(图7)显示，给药7天后，病理切片显示，小鼠肝脏、肾脏和心脏的细胞结构完整，细胞核形态正常，说明基于锰的两性羧酸金属有机骨架对小鼠主要器官无明显毒性。
对于本领域的技术人员来说，可以根据以上的技术方案和构思，给出各种相应的改变和变形，而所有的这些改变和变形，都应该包括在本发明权利要求的保护范围之内。
Claims (4)
1.一种基于锰的两性羧酸金属有机骨架，其特征在于，其重复单元为[Mn2(Cdcbp)2(H2O)4]·3(H2O)。
2.一种如权利要求1所述的基于锰的两性羧酸金属有机骨架的合成方法，其特征在于，包括如下步骤：
S1、将H3CdcbpBr溶解分散在水中，用NaOH溶液将pH调至6.0～7.0，得到配体溶液；
S2、将与H3CdcbpBr等摩尔量的MnCl2溶解于水中，得到锰盐溶液；
S3、将步骤S1中得到的配体溶液和步骤S2中得到的锰盐溶液混合，过滤，滤液置于厚壁耐压瓶后转移到可编程的烘箱；烘箱的温度在4小时内从25℃平稳地升高到100℃，在100℃保持72小时，然后在48小时内冷却到室温，得到无色晶体；
S4、过滤得到所述无色晶体，用甲醇洗涤并真空干燥，得到基于锰的两性羧酸金属有机骨架。
3.根据权利要求2所述的基于锰的两性羧酸金属有机骨架的合成方法，其特征在于，H3CdcbpBr为N-(3,5-二羧酸苄基)-(3-羧酸)溴化吡啶，分子结构如下所示：
4.权利要求1所述的基于锰的两性羧酸金属有机骨架在磁共振成像造影剂中的应用。
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