CN109608505B - 一种金属钌纳米材料的制备方法及抗肿瘤药物 - Google Patents
一种金属钌纳米材料的制备方法及抗肿瘤药物 Download PDFInfo
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Abstract
本发明提供一种金属钌纳米材料的制备方法,其包括以下步骤:1)将金属钌配合物溶解于多羧酸化合物水溶液,并进行超声波分散,得到混合液A,其中,金属钌配合物由含氨基的多吡啶配体与三氯化钌配位形成;2)将混合液A进行水浴加热,得到反应液B;3)用碱性试剂调节反应液B的pH值,然后,将反应液B的上清液透析,收集透析得到的水溶液,并将水溶液冻干,即得金属钌纳米材料。本发明的金属钌纳米材料的制备方法通过氨基的质子化和水热法,将难溶于水的金属钌配合物用可溶于水的多羧酸化合物进行包裹,使得所制金属钌纳米材料水溶性好、光稳定强、荧光量子产率较高、肿瘤光动力治疗高、生物相容性好、单线态氧产率较高。
Description
技术领域
本发明涉及纳米材料技术领域,特别涉及一种金属钌纳米材料的制备方法及抗肿瘤药物。
背景技术
癌症已经成为当今世界致死率最高的疾病之一。科学家在经过多年的探索发现金属铂对于肿瘤细胞具有靶向性和光毒性,开始作为抗肿瘤药物进入人们的视线,并作为临床上治疗睾丸癌、卵巢癌、头颈肿瘤等最为广泛使用的药物之一,但它的毒副作用也是十分明显的,如肾毒性、骨髓毒性、耳毒性、外周神经毒性、催吐性及长期使用产生的耐药性等,并且对于很多肿瘤并不起作用,使其应用受到限制。这促使部分研究者的目光转向开发非铂类金属抗癌药物。近年来很多研究认为,钌配合物是低毒性的且易于被肿瘤吸收,被认为是最有前途的抗癌药物之一。到临床研究阶段的金属钌配合物目前为止只有NAMI-A和KP1019两种,大部分的金属钌配合物存在溶解性差、合成复杂、合成原料成本高、获取的实际效益低等弊端。因此发现一种合成简便、水溶性好、应用广泛的新型金属钌纳米材料具有重要的现实意义。
发明内容
有鉴于此,本发明旨在提出一种金属钌纳米材料的制备方法,以解决现有金属钌纳米材料水溶性差、合成复杂的问题。
为达到上述目的,本发明的技术方案是这样实现的:
一种金属钌纳米材料的制备方法,包括以下步骤:
1)将金属钌配合物溶解于多羧酸化合物水溶液,并进行超声波分散,得到混合液A,其中,所述金属钌配合物由含氨基的多吡啶配体与三氯化钌配位形成;
2)将所述混合液A进行水浴加热,得到反应液B;
3)用碱性试剂调节所述反应液B的pH值,然后,将所述反应液B的上清液透析,收集透析得到的水溶液,并将所述水溶液冻干,即得金属钌纳米材料。
可选地,所述步骤1)中所述含氨基的多吡啶配体为5-氨基-1,10-邻菲罗啉、2-氨基-1,10-邻菲罗啉、2,2'-联吡啶-4,4'-二胺、2,2'-联吡啶-6,6'-二胺、2,2'-联吡啶-4,6'-二胺、2,2':6',2”-三联吡啶-4'-胺中的一种。
可选地,所述步骤1)中所述多羧酸化合物水溶液为柠檬酸水溶液、苹果酸水溶液、草酸水溶液中的一种。
可选地,所述步骤1)中所述金属钌配合物与所述多羧酸化合物的质量比为1∶50~1∶500。
可选地,所述步骤1)中所述多羧酸化合物水溶液中多羧酸化合物的质量浓度为0.05g/mL~1g/mL。
可选地,所述步骤1)中所述超声波分散的分散时间为10~40min。
可选地,所述步骤2)中所述水浴加热的加热温度为140~220℃,加热时间为1~5h。
可选地,所述步骤3)中所述用碱性试剂调节所述反应液B的pH值,包括用碱性试剂调节所述反应液B的pH值至6.8~7.4。
可选地,所述步骤3)中所述透析的截留分子量为3500Da,透析时间为2~48h。
本发明的另一目的在于提供一种抗肿瘤药物,该抗肿瘤药物包括上述金属钌纳米材料的制备方法制备的金属钌纳米材料。
相对于现有技术,本发明所述的金属钌纳米材料的制备方法具有以下优势:
1、本发明的金属钌纳米材料的制备方法通过氨基的质子化和水热法,将难溶于水的金属钌配合物用可溶于水的多羧酸化合物进行包裹,使得所制金属钌纳米材料具有良好的水溶性,从而有利于提高其生物相容性和肿瘤光动力治疗效果。
2、采用本发明的金属钌纳米材料的制备方法制得金属钌纳米材料光稳定强、荧光量子产率较高、肿瘤光动力治疗效果好、生物相容性好、单线态氧产率较高,使其可用于生物的荧光成像和抗肿瘤药物等,应用范围广。
3、本发明的金属钌纳米材料的制备方法反应原料易得、合成方法简单,易于工业化生产。
附图说明
构成本发明的一部分的附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的紫外-可见吸收光谱图;
图2为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的荧光发射光谱和激发光谱图。
图3为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的红外光谱图;
图4为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的透射电子显微镜(TEM)图像;
图5为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的X射线粉末衍射(XRD)图谱;
图6为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的X射线光电子能谱分析(XPS)全图谱;
图7为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料中碳(C)的高分辨X射线光电子能谱分析(XPS)图谱;
图8为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料中钌(Ru)的高分辨X射线光电子能谱分析(XPS)图谱;
图9为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料的单线态氧生成能力测试图像;
图10为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料与斑马鱼幼虫培养一段时间后的明场图像(图10(a))和荧光图像(图10(b));
图11为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料与HeLa细胞培养一段时间后的激光扫描共聚焦显微镜图像,其中,图11(a)为未经光照射的HeLa细胞图,图11(b)为经488nm激发波长的光照射的HeLa细胞荧光成像图,图11(c)为用 GreenDND-26(50μM)探针(绿色)进行溶酶体染色的HeLa细胞图,图11(d)为用 GreenDND-26(50μM)探针(绿色)进行溶酶体染色且经488nm激发波长的光照射的HeLa细胞荧光成像图;
图12为本发明实施例1所述的金属钌纳米材料的制备方法制得的金属钌纳米材料对HeLa细胞的暗毒性(dark)和光毒性(light)测试趋势图。
具体实施方式
需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
下面将结合附图和实施例来详细说明本发明。
实施例1
一种金属钌纳米材料的制备方法,其具体包括以下步骤:
1)将10mg金属钌配合物溶解于柠檬酸水溶液中,并进行超声波分散,得到混合液A,其中,金属钌配合物由5-氨基-1,10-邻菲罗啉与三氯化钌配位形成;柠檬酸水溶液中柠檬酸的质量为2.0g,水的体积为20mL;超声波分散的分散时间为20min,此时,金属钌配合物与柠檬酸质量比为1∶200,柠檬酸水溶液中柠檬酸的质量浓度为0.1g/mL,柠檬酸水溶液中柠檬酸的质量浓度是指柠檬酸在水中的质量浓度,即柠檬酸水溶液中柠檬酸的质量除以柠檬酸水溶液中水的体积;
2)将混合液A在185℃的水热釜中水浴加热3h,得到反应液B;
3)待反应液B冷却后,用饱和碳酸钠调节反应液B的pH值至7.0,然后,用截留分子量为3500Da的透析袋将反应液B的上清液透析24h,收集透析得到的水溶液,并将水溶液冻干,即得金属钌纳米材料(Ru-NPs)。
本实施例的金属钌纳米材料的制备方法先通过5-氨基-1,10-邻菲罗啉与三氯化钌配位制得金属钌配合物,可使金属钌配合物中的钌元素以一种配合物的方式保留在终产物Ru-NPs中。,另外金属钌配合物在不借助于有机溶剂的情况下以氨基质子化的方式溶解在柠檬酸水溶液中。然后,通过水热法使金属钌配合物与柠檬酸形成酰胺键,高温下柠檬酸分解形成一系列暴露在外围且溶于水的官能团(-OH,-COOH等),将金属钌配合物包裹起来,从而使得所制金属钌纳米材料具有较高的水溶性,进而使其具有较高的生物相容性。另外,由于金属钌配合物保留在Ru-NPs中,使得其具有高的肿瘤光动力治疗效果。且由于金属钌配合物具有良好的红光发射,使其具有良好的生物荧光成像效果。
实施例2
本实施例与实施例1的区别在于:含氨基的多吡啶配体为2-氨基-1,10-邻菲罗啉。
实施例3
本实施例与实施例1的区别在于:含氨基的多吡啶配体为2,2'-联吡啶-4,4'-二胺。
实施例4
本实施例与实施例1的区别在于:含氨基的多吡啶配体为2,2'-联吡啶-6,6'-二胺。
实施例5
本实施例与实施例1的区别在于:含氨基的多吡啶配体为2,2'-联吡啶-4,6'-二胺。
实施例6
本实施例与实施例1的区别在于:多羧酸化合物水溶液为苹果酸水溶液。
实施例7
本实施例与实施例1的区别在于:多羧酸化合物水溶液为草酸水溶液。
实施例8
一种抗肿瘤药物,该抗肿瘤药物包括上述金属钌纳米材料的制备方法制备的金属钌纳米材料。
将实施例1制得的金属钌纳米材料(Ru-NPs)溶于水,测定其紫外吸光光谱,并与溶于二氯甲烷的金属钌配合物([Ru(NH2-Phen)3](PF6)2)溶液的紫外-可见吸收光谱对比,其中,溶于二氯甲烷的金属钌配合物([Ru(NH2-Phen)3](PF6)2)与实施例1中的金属钌配合物为同一种物质,测定结果如图1所示。
由图1可知,与[Ru(NH2-Phen)3](PF6)2相比,实施例1制得的Ru-NPs在紫外区表现出钝化的无结构的吸收光谱,高能紫外区(~260nm)的吸收峰可归结于碳纳米颗粒的特征吸收,来源于sp2杂化平面的π-π*跃迁,在可见光区(~465nm),实施例1制得的Ru-NPs的吸收与[Ru(NH2-Phen)3](PF6)2类似,只是光谱稍微变宽,强度降低,表明金属钌配合物中的钌吡啶配位单元在实施例1制得的金属钌纳米材料中仍然保留。
测定实施例1制得的金属钌纳米材料(Ru-NPs)的水溶液在不同激发波长下的荧光发射光谱和激发光谱,测定结果如图2所示。
由图2可知,在不同激发波长下,红光发射峰(615nm)的位置并未发生明显变化,只是强度略有不同,表明实施例1制得的Ru-NPs的发射仍然来源于金属钌配合物的红光发射。
将实施例1制得的金属钌纳米材料(Ru-NPs)固体用KBr压片,并测定其红外光谱,测定结果如图3所示。
由图3可知,实施例1制得的金属钌纳米材料(Ru-NPs)中含有-COOH、-OH等含氧亲水官能团。。
测定实施例1制得的金属钌纳米材料(Ru-NPs)的透射电镜图像(TEM),测定结果如图4所示。
由图4可知,实施例1制得的金属钌纳米材料(Ru-NPs)具有很好的分散性,纳米颗粒呈球形,其粒径在5nm左右。
测定实施例1制得的金属钌纳米材料(Ru-NPs)和金属钌配合物([Ru(NH2-Phen)3](PF6)2)的XRD图谱,测定结果如图5所示。
由图5可知,实施例1制得的金属钌纳米材料只在20°左右出现一个很宽的衍射峰,而金属钌配合物的XRD图谱表现出较为精细的峰型,表明实施例1制得的金属钌纳米材料由一系列高度无序的碳原子组成,且金属钌配合物变成纳米颗粒后,其晶型消失。
测定实施例1制得的金属钌纳米材料(Ru-NPs)的XPS图谱,测定结果如图6所示。
由图6可知,实施例1制得的金属钌纳米材料主要由C、N、O和Ru等元素组成,286.8eV、402.4eV和534.7eV处的峰分别归属于C1s、N 1s和O1s,284.1eV对应为Ru 3d5/2的峰。
测定实施例1制得的金属钌纳米材料(Ru-NPs)中碳(C)的高分辨XPS图谱,测定结果如图7所示。
由图7可知,实施例1制得的金属钌纳米材料含有C=C(286.8eV)、C-O(287.8eV)和C=O(290eV)等官能团。
测定实施例1制得的金属钌纳米材料(Ru-NPs)中钌(Ru)的高分辨XPS图谱,测定结果如图8所示。
由图8可知,实施例1制得的金属钌纳米材料Ru3d5/2的峰裂分为464.5eV和486.0eV两个峰,分别归属为Ru 3p3/2和Ru 3p1/2,表明实施例1制得的金属钌纳米材料中金属钌的存在。
对实施例1制得的金属钌纳米材料(Ru-NPs)进行DCFH光照实验,并与金属钌配合物([Ru(NH2-Phen)3](PF6)2)、磷酸盐缓冲溶液(PBS)进行对比,以测试其单线态氧生成能力,测试结果如图9所示。
由图9可知,实施例1制得的金属钌纳米材料相对于金属钌配合物具有更高的单线态氧产率。当加入抗氧化剂维生素C(VC)后,Ru-NPs的单线态氧产率明显降低,进一步说明DCFH被Ru-NPs产生的单线态氧氧化。
将实施例1制得的金属钌纳米材料(Ru-NPs)与斑马鱼幼虫培养一段时间(0h、1h、2h),并对其明场图像和荧光图像进行测试,其中,Ru-NPs的浓度为0.5mg/mL,测试结果如图10所示,其中,图10(a)为明场图像,图10(b)为荧光图像。
由图10(a)可知,实施例1制得的金属钌纳米材料可快速进入活体内,且由图10(b)可知,斑马鱼幼虫与Ru-NPs培养一段时间后,出现了明显的红光,说明实施例1制得的金属钌纳米材料可用作活体红光成像。
将实施例1制得的金属钌纳米材料(Ru-NPs)与HeLa细胞培养一段时间(4h),采用激光扫描共聚焦显微镜对其进行测试,并用 GreenDND-26(50μM)探针(绿色)对HeLa细胞的溶酶体进行染色,然后,采用激光扫描共聚焦显微镜对其进行测试,激光扫描共聚焦显微镜的激发波长为488nm,测试结果如图11所示,其中,图11(a)为空白样,即未经光照射的HeLa细胞图,图11(b)为经488nm激发波长的光照射的HeLa细胞荧光成像图,图11(c)为用 GreenDND-26(50μM)探针(绿色)进行溶酶体染色的HeLa细胞图,图11(d)为用 GreenDND-26(50μM)探针(绿色)进行溶酶体染色且经488nm激发波长的光照射的HeLa细胞荧光成像图。
由图11(a)和图11(b)可知,HeLa细胞与Ru-NPs培养4h后出现了明显的红光,表明实施例1制得的金属钌纳米材料较易被肿瘤细胞吸收。由图11(c)和图11(d)可知,经细胞定位实验显示:用 Green DND-26标记肿瘤细胞的溶酶体后,Ru-NPs的红光与溶酶体探针的绿光基本重叠,说明实施例1制得的金属钌纳米材料主要进入到肿瘤细胞的溶酶体内。
采用MTT法测试实施例1制得的金属钌纳米材料(Ru-NPs)对HeLa细胞的(dark)和光毒性(light),其中,Ru-NPs的浓度区间为0-250μg/mL,测试结果如图12所示。
由图12可知,在白光(6.5mW/cm2)的照射下,随着Ru-NPs浓度的增加,细胞的存活率逐渐下降。当Ru-NPs的浓度为250μg/mL时,HeLa细胞的存活率仅为17%,表明实施例1制得的金属钌纳米材料具有较强的光毒性。反之,在黑暗条件下,与250μg/mL的Ru-NPs培养相同条件,HeLa细胞的存活率超过了90%,表明实施例1制得的金属钌纳米材料本身对肿瘤细胞表现出较弱的暗毒性。
以上仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种金属钌纳米材料的制备方法,其特征在于,包括以下步骤:
1)将金属钌配合物溶解于多羧酸化合物水溶液,并进行超声波分散,得到混合液A,其中,所述金属钌配合物由含氨基的多吡啶配体与三氯化钌配位形成,所述含氨基的多吡啶配体为5-氨基-1,10-邻菲罗啉;
2)将所述混合液A进行水浴加热,得到反应液B;
3)用碱性试剂调节所述反应液B的pH值,然后,将所述反应液B的上清液透析,收集透析得到的水溶液,并将所述水溶液冻干,即得金属钌纳米材料。
2.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤1)中所述多羧酸化合物水溶液为柠檬酸水溶液、苹果酸水溶液、草酸水溶液中的一种。
3.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤1)中所述金属钌配合物与所述多羧酸化合物的质量比为1∶50~1∶500。
4.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤1)中所述多羧酸化合物水溶液中多羧酸化合物的质量浓度为0.05g/mL~1g/mL。
5.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤1)中所述超声波分散的分散时间为10~40min。
6.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤2)中所述水浴加热的加热温度为140~220℃,加热时间为1~5h。
7.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤3)中所述用碱性试剂调节所述反应液B的pH值,包括用碱性试剂调节所述反应液B的pH值至6.8~7.4。
8.根据权利要求1所述的金属钌纳米材料的制备方法,其特征在于,所述步骤3)中所述透析的截留分子量为3500Da,透析时间为2~48h。
9.一种抗肿瘤药物,其特征在于,包括权利要求1至8中任一项所述的金属钌纳米材料的制备方法制备的金属钌纳米材料。
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