CN114984875A - 一种金属-酰肼配位自组装纳米球及其制备方法与应用 - Google Patents

一种金属-酰肼配位自组装纳米球及其制备方法与应用 Download PDF

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CN114984875A
CN114984875A CN202210820957.5A CN202210820957A CN114984875A CN 114984875 A CN114984875 A CN 114984875A CN 202210820957 A CN202210820957 A CN 202210820957A CN 114984875 A CN114984875 A CN 114984875A
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胥伟军
钱军民
王太兵
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Xian Jiaotong University
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Abstract

本发明公开了一种金属‑酰肼配位自组装纳米球及其制备方法与应用，将金属离子溶液与含酰肼基团的有机小分子溶液混匀，搅拌反应后离心，得到金属‑酰肼自组装纳米球。其中，金属离子来源为氯化铁、氯化亚铁、硫酸铁、硫酸亚铁、氯化铜、硝酸铜、硫酸铜、氯化锌、硝酸银、硝酸铬、氯化钆、氯化锰、氯化铕或氯金酸。本发明的金属‑酰肼自组装纳米球通过金属离子和酰肼基团间的无限配位作用制备得到，具有制备工艺简单、快速、温和的优点，只需一步反应即可制备出具有实心或中空结构的纳米球，该纳米球具有酸响应解离性，粒径范围在10纳米～300纳米范围可控，分散性良好，在制备抗肿瘤药物中具有良好应用前景。

Description

一种金属-酰肼配位自组装纳米球及其制备方法与应用
技术领域
本发明属于纳米生物材料领域，具体涉及一种金属-酰肼配位自组装纳米球及其制备方法与应用。
背景技术
纳米粒子由于具有高渗透长滞留效应引起的被动靶向效应，使其非常适合作为运输载体向癌细胞输送药物。合成粒径均匀、尺寸可控的纳米颗粒在科学研究和技术应用上都具有重要意义。传统的纳米粒子制备方法包括物理法、化学法和生物法三大类。其中，物理法中最常见的便是利用机械球磨，但存在制得样品尺寸较大，且尺寸分布不均匀，能耗较高等缺点。化学法包括微乳液法、溶胶凝胶法和水热合成法等。微乳液法和溶胶凝胶法存在操作过程较为复杂，反应周期长，且产量较小，副产物较难处理等问题。水热合成法则存在需要高温高压作为反应条件的缺点。生物法存在的问题在于难以控制纳米粒子尺寸和避免团聚。由于传统的纳米粒子制备方法或多或少都会存在一些问题，金属-有机配位自组装作为一种新方法逐渐受到研究人员的关注。
金属-有机配位自组装纳米粒子由于粒径大小可控、合成简单、表面积高等性质，在生物成像、药物释放、有机催化和气体吸附等领域有着广泛的应用。纳米金属有机框架作为其中的典型材料用于药物输送载体已被广泛探索，其自身孔道可以高效负载药物，金属配位键使得其具备酸响应降解性，有利于药物的释放。然而，其制备过程中常常需要加入大量的表面活性剂(例如聚乙烯吡咯烷酮)，导致其比表面积大幅下降，限制了其生物医学应用。而且，目前金属-有机配位自组装纳米粒子往往仅适用于单一或少数几种金属离子或有机配体，应用范围有限。
发明内容
本发明的目的是提供一种金属-酰肼配位自组装纳米球及其制备方法与应用，解决了现有金属-有机配位自组装纳米球制备方法复杂、粒径分布不均匀、金属离子适用范围窄的难题。
一种金属-酰肼自组装纳米球的制备方法，将金属离子溶液与含酰肼基团的有机小分子溶液混匀，搅拌反应后离心，得到金属-酰肼自组装纳米球。
本发明进一步的改进在于，金属离子来源为氯化铁、氯化亚铁、硫酸铁、硫酸亚铁、氯化铜、硝酸铜、硫酸铜、氯化锌、硝酸银、硝酸铬、氯化钆、氯化锰、氯化铕或氯金酸。
本发明进一步的改进在于，含酰肼基团的有机小分子为3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、乙二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼、己二酸二酰肼、癸二酸二酰肼、间苯二甲酸二酰肼、对苯二甲酸二酰肼、柠檬酸三酰肼或1,3,5-苯三甲酰肼。
本发明进一步的改进在于，金属离子溶液与含酰肼基团的有机小分子溶液的溶剂为水、甲醇、乙醇或丙醇。
本发明进一步的改进在于，金属离子溶液浓度为0.01摩尔/升～0.5摩尔/升，含酰肼基团的有机小分子溶液浓度为0.001摩尔/升～0.1摩尔/升，金属离子与含酰肼基团的有机小分子摩尔比为1:50～1:0.5。
本发明进一步的改进在于，反应温度为20摄氏度～70摄氏度，反应时间为1小时～48小时。
本发明进一步的改进在于，离心速度为5000转/分钟～20000转/分钟，离心时间为5分钟～30分钟。
一种根据如上所述的方法制备的金属-酰肼自组装纳米球，该纳米球具有实心或中空结构，粒径在10纳米～300纳米范围内。
一种如上所述的金属-酰肼自组装纳米球在制备用于抗肿瘤药物及造影剂中的应用。
本发明进一步的改进在于，抗肿瘤药物为抗乳腺癌药物。
与现有技术相比，本发明的有益效果在于：
本发明的金属-酰肼配位自组装纳米球是通过金属离子和酰肼基团间的无限配位作用制备得到的，这种配位反应对金属离子无特异选择性，适用金属离子种类多，通过选择不同的金属离子能便捷地调控纳米球中的金属种类，从而赋予纳米球不同的功能。本发明具有制备工艺简单、快速、温和的优点，只需一步反应即可制备出具有实心或中空结构的纳米球，
进一步的，本发明的金属-酰肼配位自组装纳米球通过在水相或有机相中直接混合酰肼分子和金属离子即可得到，原料易得、反应过程简单。
本发明通过调控酰肼分子和金属离子浓度即可获得具有实心或中空结构的金属-酰肼配位自组装纳米球，该纳米球分散性良好，具有酸响应解离性，粒径范围在10纳米～300纳米范围可控。
本发明的金属-酰肼配位作用具有酸响应性，使得本发明的金属-酰肼配位自组装纳米球可在肿瘤弱酸性微环境中特异性降解，释放金属离子用于成像及肿瘤治疗。
附图说明
图1是实施例1合成的铜-酰肼自组装纳米球的透射电子显微镜照片；
图2是实施例1合成的铜-酰肼自组装纳米球的氮气吸附曲线及孔径分布图(插图)；
图3是实施例1合成的铜-酰肼自组装纳米球的X射线衍射谱图；
图4是实施例1合成的铜-酰肼自组装纳米球对小鼠乳腺癌细胞4T1的杀伤效果图。
图5是实施例4合成的亚铁-酰肼自组装纳米球的透射电子显微镜照片；
图6是实施例4合成的亚铁-酰肼自组装纳米球经尾静脉注射进入小鼠后，小鼠肿瘤处的磁共振图像；其中，(a)为注射前，(b)为注射24小时后；
图7是实施例5合成的亚铁-酰肼自组装纳米球的透射电子显微镜照片。
具体实施方式
下面将结合具体实施例对本发明进行进一步阐述，显然，所描述的实施例仅仅是本发明的一部分，而不是本发明的全部实施例，所描述的实施例用于说明本发明而不用于限制本发明的范围。
本发明的一种金属-酰肼自组装纳米球的制备方法，包括以下步骤：
将浓度为0.01摩尔/升～0.5摩尔/升的金属离子溶液与浓度为0.001摩尔/升～0.1摩尔/升的含酰肼基团的有机小分子溶液混匀，20摄氏度～70摄氏度搅拌反应1小时～48小时后，5000转/分钟～20000转/分钟离心5分钟～30分钟得到金属-酰肼自组装纳米球。
其中，所述的金属离子来源为氯化铁、氯化亚铁、硫酸铁、硫酸亚铁、氯化铜、硝酸铜、硫酸铜、氯化锌、硝酸银、硝酸铬、氯化钆、氯化锰、氯化铕或氯金酸。
所述的含酰肼基团的有机小分子为3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、乙二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼、己二酸二酰肼、癸二酸二酰肼、间苯二甲酸二酰肼、对苯二甲酸二酰肼、柠檬酸三酰肼或1,3,5-苯三甲酰肼。
所述的金属离子与含酰肼基团的有机小分子摩尔比为1:50～1:0.5。
所述的金属离子溶液与含酰肼基团的有机小分子溶液的溶剂为水、甲醇、乙醇或丙醇。
采用上述方法获得的金属-酰肼自组装纳米球具有实心或中空结构，粒径在10纳米～300纳米范围内可控，分散性良好，可用于制备抗肿瘤药物及造影剂。
下面为具体实施例。
实施例1
将浓度为0.4摩尔/升的氯化铜水溶液与浓度为0.04摩尔/升的3,3'-二硫代二丙酰肼水溶液混匀，氯化铜与3,3'-二硫代二丙酰肼的摩尔比为1:4，25摄氏度反应12小时后，18000转/分钟离心10分钟，得到铜-酰肼自组装纳米球。
从图1可以看出，得到的铜-酰肼自组装纳米球分散性良好，粒径约为40纳米。
从图2可以看出，得到的铜-酰肼自组装纳米球具有多孔结构，其孔径约为2.32纳米。
从图3可以看出，得到的铜-酰肼自组装纳米球中有铜、碳、氮、氧及硫元素。
铜-酰肼自组装纳米球对肿瘤细胞杀伤效果研究。采用细胞活力检测试剂盒(CCK-8)来检测铜-酰肼自组装纳米球对小鼠乳腺癌4T1细胞的杀伤效果。将4T1细胞以5×103个细胞/孔的密度接种于96孔板上。常规培养24小时后，向各孔加入不同浓度的纳米粒子继续培养24小时。然后向每孔加入10微升CCK-8试剂并继续培养1小时，采用酶标仪检测每个孔在450纳米处的吸光度。实验组吸光度相对对照组(纳米药物浓度为0)吸光度的百分比为细胞活力。从图4可以看出，随着铜-酰肼自组装纳米球浓度升高，4T1细胞活力逐渐下降。当铜-酰肼自组装纳米球浓度为42微克/毫升时，4T1细胞活力为46.5％，说明铜-酰肼自组装纳米球可有效杀死肿瘤细胞，该纳米球可以用于制备抗肿瘤药物中，抗肿瘤药物为抗乳腺癌药物。
实施例2
将浓度为0.4摩尔/升的硫酸铜水溶液与浓度为0.04摩尔/升的3,3'-二硫代二丙酰肼水溶液混匀，氯化铜与3,3'-二硫代二丙酰肼的摩尔比为1:4，50摄氏度反应2小时后，10000转/分钟离心10分钟，得到铜-酰肼自组装纳米球。
实施例3
将浓度为0.4摩尔/升的氯化铜水溶液与浓度为0.04摩尔/升的3,3'-二硫代二丙酰肼水溶液混匀，氯化铜与3,3'-二硫代二丙酰肼的摩尔比为1:1，60摄氏度反应1小时后，12000转/分钟离心10分钟，得到铜-酰肼自组装纳米球。
实施例4
将浓度为0.4摩尔/升的氯化亚铁乙醇溶液与浓度为0.002摩尔/升的3,3'-二硫代二丙酰肼乙醇溶液混匀，氯化亚铁与3,3'-二硫代二丙酰肼的摩尔比为1:2，25摄氏度反应12小时后，18000转/分钟离心10分钟，得到亚铁-酰肼自组装纳米球。
从图5可以看出，得到的亚铁-酰肼自组装纳米球分散性良好，粒径约为68纳米。
亚铁-酰肼自组装纳米球磁共振成像效果评价。将100微升含3×106个4T1细胞的PBS缓冲液皮下注射到雌性小鼠右后侧处，待肿瘤体积长至约100立方毫米时，将100微升5毫克/毫升的亚铁-酰肼自组装纳米经尾静脉注射进入小鼠。分别在注射前及注射后24小时，拍摄小鼠T2磁共振图像。
从图6中(a)和(b)可以看出，注射纳米药物24小时后，肿瘤处可观测到清晰的T2加权磁共振信号，说明亚铁-酰肼自组装纳米球可以进入肿瘤并用于肿瘤成像，可以作为造影剂使用。
实施例5
将浓度为0.4摩尔/升的氯化亚铁乙醇溶液与浓度为0.004摩尔/升的3,3'-二硫代二丙酰肼乙醇溶液混匀，氯化亚铁与3,3'-二硫代二丙酰肼的摩尔比为1:2，30摄氏度反应12小时后，18000转/分钟离心10分钟，得到亚铁-酰肼自组装纳米球。
从图7可以看出，得到的亚铁-酰肼自组装纳米球具有中空结构，粒径约为120纳米。
实施例6
将浓度为0.1摩尔/升的氯化钆甲醇溶液与浓度为0.002摩尔/升的丙二酸二酰肼甲醇溶液混匀，氯化钆与丙二酸二酰肼的摩尔比为1:10，40摄氏度反应24小时后，10000转/分钟离心20分钟，得到钆-酰肼自组装纳米球。
实施例7
将浓度为0.05摩尔/升的氯化锰丙醇溶液与浓度为0.002摩尔/升的间苯二甲酸二酰肼丙醇溶液混匀，氯化锰与间苯二甲酸二酰肼的摩尔比为1:5，60摄氏度反应24小时后，10000转/分钟离心20分钟，得到锰-酰肼自组装纳米球。
实施例8
将浓度为0.01摩尔/升的氯化铁水溶液与浓度为0.001摩尔/升的2,2'-二硫代二乙酰肼水溶液混匀，氯化铁与2,2'-二硫代二乙酰肼的摩尔比为1:50，20摄氏度反应1小时后，5000转/分钟离心5分钟，得到铁-酰肼自组装纳米球。
实施例9
将浓度为0.5摩尔/升的硫酸铁水溶液与浓度为0.1摩尔/升的4,4'-二硫代二丁酰肼水溶液混匀，硫酸铁与4,4'-二硫代二丁酰肼的摩尔比为1:0.5，70摄氏度反应48小时后，20000转/分钟离心30分钟，得到铁-酰肼自组装纳米球。
实施例10
将浓度为0.2摩尔/升的氯化锌水溶液与浓度为0.07摩尔/升的乙二酸二酰肼水溶液混匀，氯化锌与乙二酸二酰肼的摩尔比为1:30，35摄氏度反应35小时后，7000转/分钟离心15分钟，得到锌-酰肼自组装纳米球。
实施例11
将浓度为0.3摩尔/升的硝酸银水溶液与浓度为0.06摩尔/升的乙二酸二酰肼水溶液混匀，硝酸银与乙二酸二酰肼的摩尔比为1:20，45摄氏度反应40小时后，9000转/分钟离心25分钟，得到银-酰肼自组装纳米球。
实施例12
将浓度为0.25摩尔/升的硝酸铬水溶液与浓度为0.005摩尔/升的癸二酸二酰肼水溶液混匀，硝酸铬与癸二酸二酰肼的摩尔比为1:25，35摄氏度反应30小时后，6000转/分钟离心15分钟，得到铬-酰肼自组装纳米球。
实施例13
将浓度为0.35摩尔/升的氯化锰水溶液与浓度为0.05摩尔/升的对苯二甲酸二酰肼水溶液混匀，氯化锰与对苯二甲酸二酰肼的摩尔比为1:35，45摄氏度反应35小时后，15000转/分钟离心20分钟，得到锰-酰肼自组装纳米球。
实施例14
将浓度为0.15摩尔/升的氯金酸甲醇溶液与浓度为0.08摩尔/升的柠檬酸三酰肼水溶液混匀，氯金酸与柠檬酸三酰肼的摩尔比为1:15，30摄氏度反应45小时后，20000转/分钟离心18分钟，得到金-酰肼自组装纳米球。
实施例15
将浓度为0.03摩尔/升的氯化铕乙醇溶液与浓度为0.07摩尔/升的1,3,5-苯三甲酰肼水溶液混匀，氯化铕与1,3,5-苯三甲酰肼的摩尔比为1:0.7，48摄氏度反应40小时后，17000转/分钟离心23分钟，得到铕-酰肼自组装纳米球。

Claims (10)

1.一种金属-酰肼自组装纳米球的制备方法，其特征在于：将金属离子溶液与含酰肼基团的有机小分子溶液混匀，搅拌反应后离心，得到金属-酰肼自组装纳米球。
2.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：金属离子来源为氯化铁、氯化亚铁、硫酸铁、硫酸亚铁、氯化铜、硝酸铜、硫酸铜、氯化锌、硝酸银、硝酸铬、氯化钆、氯化锰、氯化铕或氯金酸。
3.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：含酰肼基团的有机小分子为3,3'-二硫代二丙酰肼、2,2'-二硫代二乙酰肼、4,4'-二硫代二丁酰肼、乙二酸二酰肼、丙二酸二酰肼、丁二酸二酰肼、己二酸二酰肼、癸二酸二酰肼、间苯二甲酸二酰肼、对苯二甲酸二酰肼、柠檬酸三酰肼或1,3,5-苯三甲酰肼。
4.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：金属离子溶液与含酰肼基团的有机小分子溶液的溶剂为水、甲醇、乙醇或丙醇。
5.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：金属离子溶液浓度为0.01摩尔/升～0.5摩尔/升，含酰肼基团的有机小分子溶液浓度为0.001摩尔/升～0.1摩尔/升，金属离子与含酰肼基团的有机小分子摩尔比为1:50～1:0.5。
6.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：反应温度为20摄氏度～70摄氏度，反应时间为1小时～48小时。
7.根据权利要求1所述的一种金属-酰肼自组装纳米球的制备方法，其特征在于：离心速度为5000转/分钟～20000转/分钟，离心时间为5分钟～30分钟。
8.一种根据权利要求1～7中任意一项所述的方法制备的金属-酰肼自组装纳米球，其特征在于，该纳米球具有实心或中空结构，粒径在10纳米～300纳米范围内。
9.一种如权利要求8所述的金属-酰肼自组装纳米球在制备用于抗肿瘤药物及造影剂中的应用。
10.一种根据权利要求9所述的应用，其特征在于，抗肿瘤药物为抗乳腺癌药物。
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