CN110627835B - 一种顺磁性富勒烯-金属纳米配合物及其制备方法与应用 - Google Patents
一种顺磁性富勒烯-金属纳米配合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种顺磁性富勒烯‑金属纳米配合物及其制备方法和应用。所述顺磁性富勒烯‑金属纳米配合物是由富勒烯基纳米配体与无机金属盐通过螯合反应制得;所述的无机金属盐为硫酸锰、硝酸锰、氯化锰、碳酸锰、醋酸锰、硫酸钆、硝酸钆、氯化钆中的一种;所述的富勒烯基纳米配体是在富勒烯的碳笼表面经氮桥链接侧链,每个碳笼平均链接6‑18个侧链;所述侧链选自下列之一。本发明所述顺磁性富勒烯‑金属纳米配合物水溶性良好、顺磁性能优异,用作MRI纳米探针进行MRI成像造影增强效果显著,在纳米诊疗技术领域具有重要应用前景。
Description
技术领域
本发明属于碳纳米材料领域,涉及一类水溶性的顺磁性富勒烯-金属纳米配合物及其制备方法和应用,该水溶性的顺磁性富勒烯-金属纳米配合物可用作磁共振成像(MRI)探针。
背景技术
MRI依托纳米材料发展出高效低毒的顺磁性MRI纳米探针,实现恶性肿瘤诊断与/或早期影像介导治疗,是MRI活体成像技术研究新亮点,也是新兴纳米诊疗技术领域最活跃的研究方向之一。其中,顺磁性碳基MRI纳米探针中最常见于科技文献的是钆基金属富勒烯类MRI纳米探针。这些探针均为Gd@C82、Gd3N@C80、Gd3N@C84等钆内包富勒烯的羟基化、氨基化、Bingel衍生物。如,Gd3N@C80(OH)30(CH2CH2COOH)20、Gd3N@C80(OH)x(NH2)y、Gd@C82(OH)x(CH2CH2COOH)y和Gd@C82O14(OH)14(NH2)6等。当前,钆基金属富勒烯类MRI纳米探针应用研究的瓶颈,在于缺乏经济合理宏观量制备顺磁性钆基金属富勒烯及其水溶性衍生物的合成方法。
有研究者另辟蹊径,将富勒烯结合顺磁性金属配合物小分子发展成另一类新型顺磁性碳基MRI纳米探针。如:C60结合PEG、Gd-DTPA成首个C60类顺磁性MRI纳米探针;Gd-DOTA结合C60[C(COOH)2]5、HSA同时结合富勒烯与Gd-DTPA/Gd-DO3A形成3种C60类顺磁性MRI纳米探针,纵向弛豫率分别比Gd-DOTA、Gd-DTPA、Gd-DO3A提高9、19、19倍。有学者以富勒烯衍生物与锰卟啉构成富勒烯-锰基MRI纳米探针,纵向弛豫率提高71%。此外,富勒烯外接侧链作配体制备非水溶性的富勒烯-金属配合物已见报道。如,富勒烯Bingel衍生物侧链酯基及邻苯二酚单元中多个O原子多齿配位螯合锕系金属。此类富勒烯衍生物的侧链作配体,其柔性碳链桥联于碳笼,经键的旋转和弯曲而调整配位点位置,易于搭建结构独特、性能新颖的富勒烯-金属纳米配合物。这启示发明者,可发展水溶性的富勒烯-金属纳米配合物作顺磁性碳基MRI纳米探针。这需优先发展柔性侧链作多齿纳米配体的富勒烯水溶性衍生物,进而螯合顺磁金属,形成新型MRI纳米探针。发明者曾开辟富勒烯水溶化新方法,利用氮宾反应,发展出短直侧链末端含亲水基的水溶性富勒烯氮宾衍生物(专利号:201010522925.4、201611102767.0)。基于此,发明者进一步设计树枝化亲水叠氮化合物与富勒烯反应,预期即易产生高水溶性衍生物,其柔性侧链又易多齿配位结合金属,从而发明出性质新颖、结构奇异(树枝状柔性侧链作多齿配体)的新型水溶性富勒烯氮宾衍生物用作纳米配体。
本发明的目的就在于采用富勒烯水溶性衍生物的多臂侧链作柔性配体,直接以侧链中的多齿配位点结合顺磁性金属,经螯合反应,从而发明出一种水溶性的顺磁性富勒烯-金属纳米配合物及其制备方法。这为发展新型的顺磁性富勒烯-金属配合物用作MRI纳米探针研究提供全新思路。
发明内容
本发明要解决的首要技术问题是提供一种顺磁性富勒烯-金属纳米配合物及其制备方法与应用,该衍生物具有良好的水溶性及配位性能,可作为富勒烯基纳米配体,适于螯合多种金属离子。
为实现上述发明目的,本发明采用的技术方案为:
第一方面,本发明提供了一种顺磁性富勒烯-金属纳米配合物,是由富勒烯基纳米配体与无机金属盐通过螯合反应制得;所述的无机金属盐为硫酸锰、硝酸锰、氯化锰、碳酸锰、醋酸锰、硫酸钆、硝酸钆、氯化钆中的一种;所述的富勒烯基纳米配体是在富勒烯的碳笼表面经氮桥链接侧链,每个碳笼平均链接6-18个侧链;所述侧链选自下列之一:
作为优选,所述无机金属盐为醋酸锰或者氯化钆。
第二方面,本发明提供了一种顺磁性富勒烯-金属纳米配合物的制备方法,包括如下步骤:
(1)将富勒烯与叠氮化合物分别投料于隔绝空气的反应器,二者投料的物质的量之比为1:20~200;免添加有机溶剂,直接机械搅拌,加热反应,控制升温速率1-3℃/min,逐步升温至120~150℃,保温24~48小时,终止反应;所述叠氮化合物选自如下结构式所示的化合物中的一种:
(2)将步骤(1)的反应产物溶于水、过滤、浓缩、用截留分子量500-3500的透析袋透析、再过滤、冷冻干燥,得到纯净的富勒烯基纳米配体的固态产品;
(3)将步骤(2)所制备的富勒烯基纳米配体与无机金属盐按照物质的量之比为1:10-50分别投料于反应器,添加极性有机溶剂,隔绝空气,回流2-12小时,终止反应;去除溶剂,残留物复溶于水、用截留分子量500-10000的透析袋透析、过滤、冷冻干燥,得到纯净的顺磁性富勒烯-金属纳米配合物的固态产品。
本发明所述步骤(1)中,富勒烯为每个分子由60~96个碳原子组成的具有球状或类球状结构的碳笼,所述的富勒烯优选为C60、C70、C84、C90,更优选C60或C70,并以C60为最优。
本发明所述步骤(1)中,使用的叠氮化合物在室温时呈液态。
本发明所述步骤(1)中,叠氮化合物相对于富勒烯的投料比必须介于指定范围之内,即物质的量之比为20~200:1。低于该指定投料比20:1下限时,反应极易固化,易获得加成数目少的非水溶性衍生物,而难以获得水溶性衍生物;超过200:1上限时,后续纯化操作困难,且极难获得纯化产品。
本发明所述步骤(3)中,采用的极性有机溶剂优选为下列一种或几种的组合:甲醇、乙醇、丙二醇、乙腈、冰醋酸。
本发明中得到的水溶性富勒烯氮宾衍生物,由碳笼表面通过氮原子桥联柔性侧链提供多齿配位点作为富勒烯纳米配体,直接螯合顺磁性金属,同时侧链链内及链末端键联的亲水基团,使得整个富勒烯-金属配合物仍然具备水溶性,由此构建基于富勒烯配体的新型碳基MRI纳米探针,以应用于MRI影像诊疗技术领域。
因此,本发明提供了所述顺磁性富勒烯-金属纳米配合物作为MRI造影剂的应用。
与现有技术相比,本发明的有益效果在于:
(A)本发明所获得顺磁性富勒烯-金属配合物具备良好的水溶性,亦表现出良好顺磁性质,作为碳基MRI纳米探针造影增强MRI影像效果显著,在纳米诊疗技术领域具有重要应用前景。
(B)本发明提供的顺磁性富勒烯-金属纳米配合物的制备方法简便,即由多臂侧链短直碳链内含N、O或支链且末端均含亲水基,并能提供多齿配位点的水溶性富勒烯氮宾衍生物直接螯合顺磁性金属离子;该方法合成工艺操作简单、纯化分离便利、收率高效,易于工业化宏观量制备。
附图说明
图1.实施例1中C60(NCH2CH2OCH2CH2OH)8粉末的FT-IR谱图。
图2.实施例1中C60(NCH2CH2OCH2CH2OH)8粉末的热重分析谱图。
图3.实施例1中C60(NCH2CH2OCH2CH2OH)8溶液与粉末的ESR谱图。
图4.实施例1中C60(NCH2CH2OCH2CH2OH)8-Mn配合物溶液与粉末的ESR谱图。
图5.实施例1中C60(NCH2CH2OCH2CH2OH)8-Mn配合物粉末的FT-IR谱图。
图6.C60(NCH2CH2OCH2CH2OH)8-Mn配合物的T1加权MRI像(a)及质子纵向弛豫率(b)。
具体实施方式
以下实施例有助于进一步理解本发明,但本发明保护范围并不限于列举的实施例。
以下实施例中所述实验方法均为常规方法;所述试剂和材料均可从商业途径获得。其中,富勒烯C60和C70来源于河南省濮阳市永新富勒烯科技有限公司,纯度高于99.9%。所需的短直碳链内含N、O或含支链且末端均含亲水基的室温时呈液态的叠氮化合物,参考现有科技文献合成。
实施例1:制备C60(NCH2CH2OCH2CH2OH)8-Mn配合物
将360mg C60与液态的N3CH2CH2OCH2CH2OH按化学计量比(摩尔比)1:100依次投料于三口反应瓶,氮气保护,机械搅拌,控制升温速率1℃/min,缓慢升温至120℃,保温24小时,停止反应,产物冷却至室温后溶于500ml水、过滤、浓缩、截留分子量500透析袋透析、再过滤、冷冻干燥,得固化的富勒烯基纳米配体1;将0.1544g富勒烯基纳米配体1与0.186g四水合醋酸锰按照摩尔比1:10分散于200ml甲醇,隔绝空气,回流12小时,终止反应,蒸除甲醇后复溶于水,截留分子量3500透析袋透析、过滤、冷冻干燥,得到纯净的顺磁性富勒烯-锰纳米配合物1产品C60(NCH2CH2OCH2CH2OH)8-Mn。
如图1所示,红外光谱在3420cm-1处的强吸收峰归属为O-H伸缩振动,在2920、2870cm-1处的弱吸收峰归属于-CH2CH2-伸缩振动,在1640cm-1处的强吸收峰归属于C60碳笼中残余的C=C伸缩振动,1120cm-1处吸收峰归属于醚键(C-O-C)、1060cm-1归属于伯醇(C-OH)伸缩振动。IR谱图证明富勒烯基纳米配体1分子中碳笼结构及侧链-NCH2CH2OCH2CH2OH的存在。
如图2所示,TG-DTG-DSC同步分析结果表明,富勒烯基纳米配体1分子在温度区间102-762℃百分比质量从93.78%减少到44.15%,此区间减少的百分比质量(49.63%)完全归因于其分子外接侧链的全部丢失,而762℃时残留的质量则归属于C60碳笼,其中碳笼式量为720,全部外接侧链-NCH2CH2OCH2CH2OH的式量为103x,计算x=7.86,据此得富勒烯基纳米配体1平均分子式为C60(NCH2CH2OCH2CH2OH)8。
如图3所示,ESR测试C60(NCH2CH2OCH2CH2OH)8溶液及粉末样品均显示其为稳定自由基,且均为单重峰信号。
如图4所示,ESR测试富勒烯-锰纳米配合物1溶液及粉末样品均显示其为稳定自由基,其中,粉末样品显示为饱和的单重峰信号,但溶液样品则显示为Mn离子独特的六重峰信号,证实富勒烯-锰纳米配合物1样品中存在Mn元素。
如图5所示,富勒烯-锰纳米配合物1红外光谱存在Mn-O键的振动信号,此外,醚键(C-O-C)、伯醇(C-OH)伸缩振动也发生相应的位移,这也证实富勒烯配体与顺磁性金属锰成功形成配合物。
实施例2:制备C70(NCH2CH2OCH2CH2OH)10-Mn配合物
参照实施例1,将420mg C70与液态的N3CH2CH2OCH2CH2OH按化学计量比(摩尔比)1:100依次投料于三口反应瓶,其余条件同本发明实施例1,得到纯净的富勒烯基纳米配体2固态产品,热重分析表征其平均分子式为C70(NCH2CH2OCH2CH2OH)10。进一步按照实施例1的操作螯合后得富勒烯-锰纳米配合物2产品C70(NCH2CH2OCH2CH2OH)10-Mn。
实施例3:制备C60(NCH2CH(OH)CH2OH)10-Mn配合物
参照实施例1,将360mg C60与液态的N3CH2CH(OH)CH2OH按化学计量比(摩尔比)1:100依次投料于三口反应瓶,其余条件同本发明实施例1,得到纯净的富勒烯基纳米配体3固态产品,热重分析表征其平均分子式为C60(NCH2CH(OH)CH2OH)10。进一步按照实施例1的操作螯合后得富勒烯-锰纳米配合物3产品C60(NCH2CH(OH)CH2OH)10-Mn。
实施例4:制备C70(NCH2CH(OH)CH2OH)12-Mn配合物
参照实施例1,将420mg C70与液态的N3CH2CH(OH)CH2OH按化学计量比(摩尔比)1:100依次投料于三口反应瓶,其余条件同本发明实施例1。得到纯净的富勒烯基纳米配体4固态产品。热重分析表征其平均分子式为C70(NCH2CH(OH)CH2OH)12;进一步按照实施例1的操作螯合后得富勒烯-锰纳米配合物4产品C70(NCH2CH(OH)CH2OH)12-Mn。
实施例5:富勒烯-锰纳米配合物作MRI造影剂弛豫性能测试的具体实施方式
弛豫性能实验在200兆动物MRI仪上进行。将实施例制备的配合物配置成一系列不同浓度的配合物溶液样品。采用反转恢复自旋回波成像序列扫描,序列参数为:重复时间10s,回波时间13.5ms,成像面积3.5×3.5cm2,片厚1.0mm,数据矩阵64×64,在0.05~15s之间选择一系列合适的TI值。通过三参数单指数函数拟合,获得所有待测样品的纵向驰豫时间T1。通过其系列不同浓度时T1值拟合其质子纵向弛豫率。图6(b)为C60(NCH2CH2OCH2CH2OH)8-Mn配合物纵向弛豫速率1/T1相对于其浓度变化趋势图,此变化趋势的斜率即为其纵向弛豫速率,值为11.37mM-1S-1。T1加权MRI像表明C60(NCH2CH2OCH2CH2OH)8-Mn配合物增强质子弛豫显著(图6(a))。实施例制备的富勒烯-锰纳米配合物的质子纵向弛豫率示于表1,其值均比文献报道的金属锰卟啉小分子配合物Mn-TSPP(Zhang,Z.,et al.,Bioorganic and Medicinal Chemistry Letters.2009;19(23):6675-6678.)的弛豫率高50%以上,这表明富勒烯纳米配体直接螯合顺磁性金属有助于体系弛豫率值的提高,用于MRI检测时造影增强效果更显著。
表1
样品名 | 质子纵向弛豫率(mM<sup>-1</sup>S<sup>-1</sup>) |
富勒烯-锰纳米配合物1 | 11.37 |
富勒烯-锰纳米配合物2 | 12.40 |
富勒烯-锰纳米配合物3 | 14.33 |
富勒烯-锰纳米配合物4 | 15.67 |
Mn-TSPP | 7.36 |
Claims (8)
2.如权利要求1所述的顺磁性富勒烯-金属纳米配合物,其特征在于:所述无机金属盐为醋酸锰或者氯化钆。
3.一种如权利要求1所述的顺磁性富勒烯-金属纳米配合物的制备方法,包括如下步骤:
(1)将富勒烯与叠氮化合物分别投料于隔绝空气的反应器,二者投料的物质的量之比为1:20~200;免添加有机溶剂,直接机械搅拌,加热反应,控制升温速率1-3℃/min,逐步升温至120~150℃,保温24~48小时,终止反应;所述叠氮化合物选自如下结构式所示的化合物中的一种:
(2)将步骤(1)的反应产物溶于水、过滤、浓缩、用截留分子量500-3500的透析袋透析、再过滤、冷冻干燥,得到纯净的富勒烯基纳米配体的固态产品;
(3)将步骤(2)所制备的富勒烯基纳米配体与无机金属盐按照物质的量之比为1:10-50分别投料于反应器,添加极性有机溶剂,隔绝空气,回流2-12小时,终止反应;去除溶剂,残留物复溶于水、用截留分子量500-10000的透析袋透析、过滤、冷冻干燥,得到纯净的顺磁性富勒烯-金属纳米配合物的固态产品。
4.如权利要求3所述的制备方法,其特征在于:步骤(1)中,所述的富勒烯为C60、C70、C84或C90。
5.如权利要求3所述的制备方法,其特征在于:步骤(1)中,所述的富勒烯为C60或C70。
6.如权利要求3所述的制备方法,其特征在于:步骤(1)中,所述的富勒烯为C60。
7.如权利要求3-6之一所述的制备方法,其特征在于:步骤(3)中,所述的极性有机溶剂为下列一种或几种的组合:甲醇、乙醇、丙二醇、乙腈、冰醋酸。
8.如权利要求1所述的顺磁性富勒烯-金属纳米配合物在制备MRI造影剂中的应用。
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