CN114949205B - 一种介孔纳米材料的制备方法及应用 - Google Patents
一种介孔纳米材料的制备方法及应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
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Abstract
本发明公开一种介孔纳米材料的制备方法及应用,采用ICG、修饰后的介孔二氧化硅制备得到,二者通过共价键接合从而得到可实现光热疗法以及生成活性氧一体化的介孔纳米材料;本发明合成的介孔纳米材料可以通过光照产生活性氧和高温来达到杀死肿瘤细胞的效果。
Description
技术领域
本发明涉及一种介孔纳米材料的制备方法及应用,属纳米材料技术领域。
背景技术
随着对活性氧(reactive oxygen species,ROS)研究的发展,大量证据表明,ROS在高剂量的时候会对细胞产生氧化应激和损伤,但生理剂量的ROS在线粒体和细胞核的交互中起到重要的信息传递作用。
纳米材料在药物领域引起了越来越多的关注,但是现阶段还没有很好的材料来促进ROS的生成。
无机材料介孔二氧化硅在结构和性能上具有独特的优势:具有可调的粒径,通过调控可以使介孔二氧化硅的粒径控制在50~300nm之间,适合于活细胞的内吞、易功能化的表面以及良好的生物相容性、低毒性等特点。
吲哚菁绿(Indocyanine Green,ICG)属于一种良好的光敏剂,经美国FDA批准可以用于临床近红外光造影剂。
发明内容
本发明提供一种介孔纳米材料的制备方法及应用,纳米材料采用ICG、修饰后的介孔二氧化硅制备得到,二者通过共价键接合从而达到可实现光热疗法以及生成活性氧一体化的纳米粒子。
本发明提供一种介孔纳米材料的制备方法,具体步骤如下:
(1)称取16g CTAC,加入200mL水,以1500rpm-1550rpm速度搅拌,油浴加热,待温度升至95℃-105℃时,加入0.5mL的TEA溶液,再加入300mg醋酸铈,随后搅拌一小时,再逐滴加入TEOS 12mL,大约半小时滴加完毕,反应1h后,以12000rpm离心30min,取沉淀加入盐酸-甲醇溶液70mL将其分散,转移至100mL圆底烧瓶中,置于油浴锅中以80℃回流6h,重复分散-回流过程3次,以12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散在水中保存,冷冻干燥后即得到掺杂醋酸铈的MSN;
(2)取1g掺杂醋酸铈的MSN,加入50mL甲苯,逐滴加入1mLAPTES,120℃回流24h,12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散于水中保存,待冷冻干燥后即得到掺杂醋酸铈的MSN-NH2;
(3)在40mL乙腈中加入1.0g 1,1,2-三甲基苯并吲哚和1.1g乙基碘,85℃加热回流24h,真空浓缩至溶液全部挥发得残留物,向残留物中加入80mL乙醚,用乙醚反复洗涤所得固体,即化合物1;
(4)向溶有5.7g的1,1,2-三甲基苯并吲哚的240mL乙腈(MeCN)中,加入8.6g 6-碘己酸,然后将混合物在105℃下加热回流4天,真空浓缩反应混合物,向残留物中加入500mL乙醚,所得固体用乙醚反复洗涤,得到化合物2;
(5)将8.0g化合物1和6.3g戊二烯醛缩二苯胺盐酸盐加入到160mL乙酸酐中,悬浮液在100℃加热1h,冷却后,将反应混合物倒入900mL水中,用水反复洗涤所得固体,得到暗红色固体即化合物3;
(6)在2mL吡啶中加入0.10g化合物2和0.15g化合物3,在40℃下搅拌30分钟,用旋转蒸发仪55℃真空除去溶剂后,残留物通过硅胶色谱纯化,用氯仿-甲醇梯度洗脱,得到深绿色固体为ICG-COOH;
(7)将68.75mg ICG-COOH和79.92mg N,N-碳酰二咪唑(CDI)溶解在10mL二甲基甲酰胺中,搅拌1小时,以活化ICG-COOH的羧基,然后将活化的溶液滴入掺杂醋酸铈的MSN-NH2-4-二甲氨基吡啶-二甲基甲酰胺溶液中,搅拌24小时后,将反应混合物在15000rmp下离心洗涤,并冻干即得到介孔纳米材料。
步骤(1)盐酸-甲醇溶液是盐酸和甲醇体积比v∶v=1∶4混合而成,盐酸的浓度是2mol/L。
步骤(6)氯仿-甲醇梯度洗脱的洗脱液是氯仿-甲醇混合液,洗脱浓度梯度是氯仿和甲醇体积比为100∶1-10∶1。
步骤(7)掺杂醋酸铈的MSN-NH2-4-二甲氨基吡啶-二甲基甲酰胺溶液是将27.33mg掺杂醋酸铈的MSN-NH2和60mg 4-二甲氨基吡啶DMAP加入到2mL二甲基甲酰胺中得到。
本发明还提供所述介孔纳米材料的应用,介孔纳米材料中的ICG作为光热疗法药物,修饰后的二氧化硅介孔起到生成ROS活性氧的作用,实现了光热疗、促进ROS生成一体的效果从而杀死肿瘤细胞。
附图说明
图1为ICG-COOH的1H-NMR谱图;
图2为傅立叶变换-红外光谱图;
图3为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3动态光散射检测图;
图4为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3的TEM图;
图5为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3的ZETA图;
图6为生理盐水、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的体外光热试验;
图7为ICG-MSN-Ce(AC)3的吸光度曲线;
图8为材料在肝癌细胞中生成ROS测定实验结果图;
图9为材料的细胞毒性实验结果图。
具体实施方式
下面通过实施例和附图进一步阐述本发明的实质性特点和显著的进步,但本发明的保护范围绝非仅局限于实施例。实施例中使用的原材料均可市场购买得到。
本发明缩写说明如下:CTAC:十六烷基三甲基氯化铵;TEA:三乙胺;TEOS:正硅酸乙酯;APTES:3-氨丙基三乙氧基硅烷;CDI:N,N-碳酰二咪唑。
实施例1
NH2-MSN-Ce(AC)3的制备方法,具体步骤如下:
(1)称取16g CTAC,加入200mL水,以1500rpm-1550rpm速度搅拌,油浴加热,待温度升至95℃-105℃时,加入0.5mL的TEA溶液,在此时加入300mg醋酸铈,随后搅拌一小时,再逐滴加入TEOS 12mL,大约半小时滴加完毕,反应1h后,以12000rpm离心30min,取沉淀加入盐酸-甲醇溶液(盐酸∶甲醇v∶v=1∶4,盐酸的浓度是2mol/L)70mL将其分散,转移至100mL圆底烧瓶中,置于油浴锅中以80℃回流6h,重复分散-回流过程3次,以12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散在水中保存,冷冻干燥后即得到掺杂醋酸铈的MSN即MSN-Ce(AC)3;
(2)取1g MSN-Ce(AC)3,加入50mL甲苯,逐滴加入1mL APTES,120℃回流24h,12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散于水中保存,待冷冻干燥后即得到掺杂醋酸铈的MSN-NH2即NH2-MSN-Ce(AC)3。
实施例2
ICG-COOH的制备方法,具体步骤如下:
(1)在乙腈(40mL)中加入1,1,2-三甲基苯并吲哚(1.0g,4.8mmol)和乙基碘(1.1g,7.2mmol),85℃加热回流24h,真空浓缩至溶液全部挥发得残留物,向残留物中加入乙醚(80mL),用乙醚反复洗涤所得固体,即化合物1,其反应过程如下Ⅰ所示;
(2)向溶有1,1,2-三甲基苯并吲哚(5.7g,27.2mmol)的乙腈MeCN(240mL)中,加入6-碘己酸(8.6g,35.4mmol),然后将混合物在105℃下加热回流4天,真空浓缩反应混合物,向残留物中加入乙醚(500mL),所得固体用乙醚反复洗涤,得到化合物2,其反应过程如下Ⅱ所示;
(3)将化合物1(8.0g,22.0mmol)和戊二烯醛缩二苯胺盐酸盐(6.3g,22.0mmol)加入到乙酸酐(160mL)中,悬浮液在100℃加热1h,冷却后,将反应混合物倒入水中(900mL),用水反复洗涤所得固体,得到暗红色固体即化合物3,其反应过程如下Ⅲ所示;
(4)在吡啶(2mL)中加入化合物2(0.10g,0.31mmol)和化合物3(0.15g,0.31mmol),在40℃下搅拌30分钟,用旋转蒸发仪55℃真空除去溶剂后,残留物通过硅胶色谱纯化,用氯仿-甲醇(氯仿∶甲醇的体积比为:100∶1、90∶1、80∶1、70∶1、60∶1、50∶1、40∶1、30∶1、20∶1、10∶1)梯度洗脱,得到深绿色固体化合物4即为ICG-COOH,其反应过程如下Ⅳ所示;
图1为ICG-COOH的1H-NMR谱图,根据图1的1H-NMR结果,1H NMR(200MHz,CDCl3)d1.4(t,J=6.8Hz,3H),1.5–2.0(m,6H),1.9(s,12H),2.4(t,J=6.6Hz,2H),4.2(m,4H),6.1(d,J=13.4Hz,1H),6.3(d,J=13.7Hz,1H),6.7(t,J=12.7Hz,2H),7.3–8.2(m,15H),表明ICG-COOH的成功合成。
实施例3
ICG-MSN-Ce(AC)3的制备方法,ICG-MSN-Ce(AC)3的合成是通过ICG-COOH的羧基和NH2-MSN-Ce(AC)3氨基之间的酰胺反应进行的,具体步骤如下:
将ICG-COOH(68.75mg,0.16mmol)和CDI(79.92mg,0.496mmol)溶解在10mL二甲基甲酰胺中,搅拌1小时以活化ICG-COOH的羧基,然后将活化的ICG溶液加入到NH2-MSN-Ce(AC)3-4-二甲氨基吡啶-二甲基甲酰胺溶液中,NH2-MSN-Ce(AC)3-4-二甲氨基吡啶-二甲基甲酰胺溶液是将NH2-MSN-Ce(AC)3(27.33mg,0.032mmol)和4-二甲氨基吡啶DMAP(60mg,0.496mmol)加入到2mL二甲基甲酰胺中得到,搅拌24小时后,将反应混合物在15000rpm下离心洗涤,并冻干即得到介孔纳米材料ICG-MSN-Ce(AC)3。
图2为ICG-COOH、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的傅立叶变换-红外光谱图,从图中可知3260cm-1和1671cm-1附近出现酰胺键吸收峰,表明ICG键接到NH2-MSN-Ce(AC)3上。
实施例4
使用Malvern zeta测径仪通过动态光散射检测MSN-Ce(AC)3、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的粒径和zeta电位,通过TEM对MSN-Ce(AC)3、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的粒径分布和形貌进行了表征。
图3为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3动态光散射检测图;图4为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3的TEM图;图5为MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC)3的Zeta图;三个图中,从左往右分别是MSN-Ce(AC)3、NH2-MSN-Ce(AC)3和ICG-MSN-Ce(AC),从动态光散射检测和TEM图像散射可以看出,粒子为粒径均在100nm左右的均匀分散的介孔二氧化硅纳米粒子;MSN-Ce(AC)3、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的Zeta电位分别是+18.1m.V、-21.3m.V、-17.5m.V,而Zeta电位的绝对值在0-25之间则表明整个纳米体系是稳定的结构,说明测试的三个系统的结构均是稳定的。
实施例5
为证明ICG-MSNs-Ce(AC)3的光热效果,将生理盐水(1mL)、NH2-MSN-Ce(AC)3(40μg/mL)1mL、ICG-MSN-Ce(AC)3(40μg/mL)1mL分别放入5mL离心管中,用808纳米激光照射(1W/cm2)照射5min,用Fotric 225-1红外热成像相机获得了最高温度。
图6为生理盐水、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的体外光热试验,从左往右分别是照射1min、2min、5min的情况,从图中可看出激光照射后生理盐水、NH2-MSN-Ce(AC)3、ICG-MSN-Ce(AC)3的最高温度分别达到37.8、37.8、62.2℃,证明ICG-MSN-Ce(AC)3的光热效应。
实施例6
选择3,3’,5,5’-四甲基联苯胺(TMB)作为·OH指示剂检测ICG-MSN-Ce(AC)3产生·OH的能力,将10mg TMB溶于10mL DMF中得到TMB溶液,10mg MSN-ICG-Ce(AC)3分散在1mL水中,再将1mL TMB溶液和1mL H2O2加到ICG-MSN-Ce(AC)3分散液中,使得三者液体混合,并在不同时间点用UV检测吸光度变化,得到ICG-MSN-Ce(AC)3纳米粒产生·OH的完整光谱曲线。
图7为ICG-MSN-Ce(AC)3的吸光度曲线,在波长350-500nm之间的曲线,从下到上依次是0、2、5、10、15、20min的吸光度曲线,从图中可以看出无色TMB会和·OH反应生成蓝色oxTMB,且具有时间的依赖性,随着时间的增加,ICG-MSN-Ce(AC)3与H2O2混合TMB使得吸光度变化曲线不断升高,说明生成蓝色oxTMB含量不断增加,表明ICG-MSN-Ce(AC)3可以不断产生·OH。
实施例7
产生活性氧的能力和细胞毒性实验:
细胞培养:将人肝癌细胞系HepG-2放置于含10%胎牛血清及1%青霉素-链霉素的DMEM培养基中,置于37℃、5%CO2培养箱中培养,每1天更换培养液1次,每2天用0.25%胰酶消化传代一次,细胞密度达到90%时,收集细胞,离心去上清,在给药前将HepG-2细胞置于20mm玻璃底皿中培养24h,然后将浓度均为25μg/mL的MSN-Ce(AC)3、ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,3min)100μL分别加入到培养皿中培养4h,用空白细胞作对照;使用2’,7’-二氯荧光素醋酸(DCFH-DA)活性氧检测试剂盒检测活性氧生成情况,将DCFH-DA(10mM,10μL)加入到不同载体的培养皿在与空白细胞(control),MSN-Ce(AC)3,ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,3min)孵育4h后通过CLSM捕获处理细胞的荧光图像,DAPI染色细胞核显示蓝色荧光,而DCFH-DA显示了绿色荧光。
用MTT(四甲基偶氮唑盐)法检测细胞抑制率,按照前面的细胞培养条件,把游离ICG、游离DOX、MSN-Ce(AC)3,ICG-MSN-Ce(AC)3,ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,3min)的浓度分别设置为6.25μg/mL,12.5μg/mL,25μg/mL,50μg/mL,100μg/mL,观察细胞贴壁后,换不同药物含量的培养液继续培养24h,并设置不含细胞的空白组,在细胞给药24h后,将96孔板从细胞培养箱中取出,向每个孔中加入5μL的MTT溶液,确保加入过程不要漏加或错加,之后,将96孔板放入细胞培养箱中,继续培养4h后,取出96孔板,将其中的培养液用移液枪吸出,同时向每个孔中加入200μL的DMSO溶液,放置在水平摇床上进行震荡混匀,5min,使甲臜结晶可以充分溶解,混匀,每组重复测定三遍,按照如下公式计算细胞增殖抑制率:
细胞生长抑制率=(1-实验组OD均值-空白对照组/细胞对照组-空白对照组OD均值)*100%。
图8为材料在肝癌细胞中生成ROS测定实验结果图,从图中可以看出,空白细胞在不经任何处理时加入DCFH-DA探针共孵育是没有绿色荧光出现,则说明并没有活性氧产生,在经MSN-Ce(AC)3,ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,3min)共孵育之后的细胞则产生了绿色荧光,说明虽然MSN-Ce(AC)3、ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,3min)都会产生活性氧,且ICG-MSN-Ce(AC)3+laser产生的活性氧更多。
图9为材料的细胞毒性实验图,根据细胞存活率来看,游离的ICG是无毒的,最大浓度的细胞存活率达到了66%,而MSN-Ce(AC)3和ICG-MSN-Ce(AC)3材料细胞最大浓度存活率在40%左右,表明对肝癌细胞有抑制作用,而ICG-MSN-Ce(AC)3+laser(808nm,1W/cm2,min)细胞存活率仅在20%左右,抗癌药物DOX最大浓度细胞存活率在30%左右,说明ICG-MSN-Ce(AC)3纳米材料加光照抑制肝癌细胞的效果最好,进一步证明了光照和功能化介孔协同杀死肿瘤的效果。
因为介孔材料还是优秀的多孔吸附性材料,还可以在介孔中空的孔道里负载抗癌药物实现光疗、ROS产生、化疗一体化的功能型纳米粒子。
Claims (4)
1.一种介孔纳米材料的制备方法,其特征在于,具体步骤如下:
(1)称取16g CTAC,加入200mL水,以1500rpm-1550rpm速度搅拌,油浴加热,待温度升至95℃-105℃,加入0.5mL的TEA,再加入300mg醋酸铈,随后搅拌1小时,再逐滴加入TEOS12mL,半小时滴加完毕,反应1h后,以12000rpm离心30min,沉淀加入盐酸-甲醇溶液70mL将其分散,转移至圆底烧瓶中,以80℃回流6h,重复分散-回流过程3次,以12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散在水中,冷冻干燥后得到掺杂醋酸铈的MSN;
(2)取1g 掺杂醋酸铈的MSN,加入50mL甲苯,逐滴加入1mLAPTES,120℃回流24h,12000rpm离心30min,再用乙醇和水分别洗涤3次,所得产物分散于水中,待冷冻干燥后即得到掺杂醋酸铈的MSN-NH2;
(3)在40mL乙腈中加入1.0g 1,1,2-三甲基苯并吲哚和1.1g乙基碘,85℃加热回流24h,真空浓缩至溶液全部挥发得残留物,用乙醚反复洗涤,即得化合物1;
(4)向溶有5.7g的1,1,2-三甲基苯并吲哚的240mL乙腈中,加入8.6g 6-碘己酸,混合物在105℃下加热回流4天,真空浓缩,所得固体用乙醚反复洗涤,得到化合物2;
(5)将8.0g化合物1和6.3g戊二烯醛缩二苯胺盐酸盐加入到160mL乙酸酐中,悬浮液在100℃加热1h,冷却后,用水反复洗涤所得固体,得到化合物3;
(6)在2mL吡啶中加入0.10g化合物2和0.15g化合物3,在40℃下搅拌30分钟,旋转蒸发仪55℃真空除去溶剂后,残留物通过硅胶色谱纯化,氯仿-甲醇梯度洗脱,得到ICG-COOH;
(7)将68.75mg ICG-COOH和79.92mg N,N-碳酰二咪唑溶解在10mL二甲基甲酰胺中,搅拌1小时,将溶液滴入掺杂醋酸铈的MSN-NH2-4-二甲氨基吡啶-二甲基甲酰胺溶液中,搅拌24小时后,反应混合物在15000rmp下离心洗涤,并冻干即得到介孔纳米材料;
步骤(7)掺杂醋酸铈的MSN-NH2-4-二甲氨基吡啶-二甲基甲酰胺溶液是将27.33mg掺杂醋酸铈的MSN-NH2和60mg 4-二甲氨基吡啶加入到2mL二甲基甲酰胺中得到。
2.根据权利要求1所述介孔纳米材料的制备方法,其特征在于,步骤(1)盐酸-甲醇溶液是盐酸和甲醇体积比1∶4混合而成,盐酸的浓度是2mol/L。
3.根据权利要求1所述介孔纳米材料的制备方法,其特征在于,步骤(6)氯仿-甲醇梯度洗脱的洗脱液是氯仿-甲醇混合液,洗脱浓度梯度是氯仿和甲醇体积比为100∶1-10∶1。
4.权利要求1所述的制备方法制备得到的介孔纳米材料在制备抗肝癌药物中的应用,介孔纳米材料通过光热疗并产生大量ROS杀死肝癌细胞。
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