CN108553644B - 基于介孔硅/环糊精/氧化锌量子点构建的双阀门多刺激响应型药物载体及其制备方法 - Google Patents
基于介孔硅/环糊精/氧化锌量子点构建的双阀门多刺激响应型药物载体及其制备方法 Download PDFInfo
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- zinc oxide
- cyclodextrin
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Abstract
本发明公开了一种基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体及其制备方法,它以介孔硅纳米粒子为载体,负载药物后,采用氨基化氧化锌量子点进行封堵,得到氧化锌量子点封堵的药物载体;接着,所得氧化锌量子点封堵的药物载体通过化学键连接二茂铁甲酸后,再与酸酐化的环糊精反应进行二次封堵,得到复合纳米药物载体系统。该复合纳米药物载体系统,具备双pH敏感、H2O2氧化敏感以及荧光成像的性质,具有更加高效的癌细胞内靶向给药能力,可以有效提高药物利用率。
Description
技术领域
本发明属于药物载体领域,具体涉及一种基于介孔硅/环糊精/氧化锌量子点构建的“双 阀门”多刺激响应型药物载体及其制备方法。
背景技术
在癌症治疗中,人们一直对刺激响应型药物载体具有浓厚兴趣,以改善治疗功效,减少 药物副作用。与聚合物纳米颗粒、胶束和脂质体相比,介孔二氧化硅纳米颗粒(MSNs)因其 表面积高、孔隙体积大、孔径可调,生物相容性好,易功能化等优点,已成为一种具有前景 的药物输送载体。基于MCM-41型介孔硅(MSNs),通过无机纳米粒子、有机分子和生物分 子在内的各种“阀门”,针对一系列刺激物,如pH、氧化还原、光和酶等研制出了各种刺激响应型药物载体,并具有很好的疗效。
目前的药物控释载体系统虽具有良好的刺激释放作用,但在诊断方面还需借助其他方 式,如X光,B超,CT等一些影像学设备的影像检测,但是经过影像学检查查出的肿瘤都是比较大的肿瘤了,基本都到了中晚期;肿瘤标志物检查,肿瘤标志物通常用作检验癌症是否复发,而不是用在健康人身上;基因检测,目前基因检测比较昂贵,且受基因样本库、专业解读水平的制约,基因检测的结果解读难度大;尿液检测,可以定性检测尿液中各氨基酸的含量,从而判断人体内恶性肿瘤细胞的代谢活跃程度,进而进行恶性肿瘤风险评估,但这种方式准确度低。所以研究一种高效、快捷、准确的诊断方式在癌症诊疗中尤其重要。
在药物控释载体系统中,常用的是单一阀门对载体进行封堵,构建刺激响应型载体,虽 然具有较好的控释作用,但由于阀门接枝率较低和载体在运输过程中长时间循环,药物载体 系统很容易发生药物的提前释放或者“泄漏”。如果构造一种双阀门多刺激响应的药物载体 系统将会大大增加药物包封效果,减少药物的提前释放。
环糊精/介孔硅药物载体在药物控释方面的研究取得了一定进展,同时也存在许多问 题,环糊精/介孔硅药物载体体系处于研发阶段,大多数研究为材料生物相容性和降解性能 以及药物释放速率的研究,缺少对环糊精酸酐化和其他纳米阀门同时构建药物载体的研究。
发明内容
本发明所要解决的技术问题是针对上述现有技术存在的不足而提供一种基于介孔硅/环 糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,具备双pH敏感、H2O2氧化 敏感以及荧光成像的性质,具有更加高效的癌细胞内靶向给药能力,可以有效提高药物利用 率。
本发明为解决上述提出的问题所采用的技术方案为:
一种基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,它以 介孔硅纳米粒子为载体,负载药物后,采用氨基化氧化锌量子点进行封堵,得到氧化锌量子 点封堵的药物载体;接着,所得氧化锌量子点封堵的药物载体通过化学键连接二茂铁甲酸 后,再与酸酐化的环糊精反应进行二次封堵,得到基于介孔硅/环糊精/氧化锌量子点构建的 “双阀门”多刺激响应型药物载体。其中,可以负载的药物主要包括阿霉素、喜树碱、紫杉 醇等。
按上述方案,所述介孔硅纳米粒子的尺寸在100-300nm范围内。
上述基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备 方法,包括如下步骤:
步骤1:制备氧化锌量子点封堵的阿霉素介孔硅载体(DOX@MSN-N-ZnO)
将羧基功能化MCM-41型介孔硅纳米粒子(MSN-COOH)分散在溶剂二氯甲烷中,然后加 入药物阿霉素(DOX),在常温下避光搅拌20-28h后,再加入N,N-二环己基碳二亚胺(DCC)、4-二甲氨基吡啶(DMAP)常温活化反应6-12h后,接着加入氨基化氧化锌量子点(ZnO-NH2QDs)反应40-56h后,经洗涤、冻干得到DOX@MSN-N-ZnO;
步骤2:制备酸酐化环糊精保护的介孔硅基药物载体(DOX@MSN-ZnO-Fc-CD-cit)
2-1、将二茂铁甲酸(Fc-COOH)分散在溶剂二氯甲烷中,加入N,N-二环己基碳二亚胺 (DCC)、4-二甲氨基吡啶(DMAP)常温活化反应6-12h;
2-2、将步骤1所得DOX@MSN-N-ZnO分散在溶剂二氯甲烷中,加入到步骤a所得溶 液中搅拌20-28h,清洗烘干后得到二茂铁甲酸修饰的搭载阿霉素氧化锌封堵的介孔硅基载体(DOX@MSN-N-ZnO-Fc);
2-3、将步骤2-2所得DOX@MSN-N-ZnO-Fc分散在去离子水中,在加入酸酐化的环糊精(β-CD-cit)冰水浴中反应20-28h后,清洗烘干,即得到酸酐化环糊精保护的介孔硅基药物载体(DOX@MSN-ZnO-Fc-CD-cit)。
按上述方案,所述氨基化氧化锌量子点(ZnO-NH2QDs)的制备方法如下:将ZnO QDs分 散在无水N’N-二甲基甲酰胺(DMF)中,加入三氨丙基三乙氧基硅烷(APTES),在110-130℃ 下反应10-30min后,用DMF离心清洗并真空干燥后,得到白色氨基化氧化锌量子点(ZnO-NH2QDs)。
按上述方案,所述步骤1中,羧基化的MSN与DOX:质量比在4:1-2:1之间,氨基化ZnO量子点的质量为羧基MSN的1-3倍。
按上述方案,所述步骤1中,溶剂二氯甲烷起分散作用,保证载体浓度在1-10mg/ml, 能将载体分散就好;4-二甲氨基吡啶与N,N-二环己基碳二亚胺摩尔比为1:5-1:10之间;以活 化剂N,N-二环己基碳二亚胺确定催化剂。
按上述方案,所述步骤2-1中,溶剂起分散作用保证载体的浓度在1-10mg/ml,此步骤 溶剂的用量可参考步骤1中溶剂二氯甲烷的用量;4-二甲氨基吡啶与N,N-二环己基碳二亚胺 摩尔比为1:5-1:10之间,且4-甲氨基吡啶与二茂铁甲酸的摩尔比为5:1-10:1。
按上述方案,所述步骤2中,步骤1所得DOX@MSN-N-ZnO与二茂铁甲酸(Fc-COOH) 的质量比为1:1-1:2之间。
步骤2-2所得DOX@MSN-N-ZnO-Fc与酸酐化的环糊精(β-CD-cit)的质量比为1:1-1:2 之间。
按上述方案,所述步骤(2)中,酸酐化的环糊精(β-CD-cit)的制备方法为:将氨基化 的环糊精溶解在去离子水中,加入二甲基马来酸酐后调节体系pH到8-9之间,30-50℃下搅 拌40-55h后,透析2-4天后冻干,得到酸酐化的环糊精β-CD-cit。其中,去离子水主要其溶 解作用保证环糊精能溶解就好,环糊精浓度为2-10mg/ml,二甲基马来酸酐与氨基化的环糊 精质量比为2:1-5:1之间。
本发明的主要原理是:本发明以介孔硅(MSN)为无机药物载体,在其负载药物后,通过 对MSN进行修饰,以化学键连接氨基化量子点ZnO作为药物阀门,然后再连接二茂铁甲酸 Fc-COOH,通过主客体作用加载酸酐化的环糊精继续进行封堵,最后将载体酸酐化,使载体呈现电负性,提高载体在体内的循环时间。其中,酸酐化的环糊精,通过主客体作用连接在载体外部,在癌细胞外弱酸性条件下(pH≈6.5)实现电荷翻转,使载体恢复到正电性, 促进细胞对载体的摄取,实现一级酸响应;引入ZnO量子点不仅可以很好的对MSN进行封 堵,ZnO量子点自身在酸性条件下水解,量子点结构瓦解,释放药物,从而实现二级酸响 应,从而构建得到“双阀门”双pH敏感的药物控释载体,命名载体为DOX@MSN-ZnO-Fc- CD-cit。并且,ZnO量子点同时具有荧光效应,药物载体通过一级酸响应在癌组织附近富集 后,通过特定波长的光激发产生荧光,通过对荧光的观测,对载体进行跟踪,最后可以判断 病灶组织,实现诊疗一体化。
与现有技术相比,本发明的有益效果是:
第一、本发明所述复合纳米药物载体系统中同时引入第一个“阀门”量子点和二茂铁Fc, 通过与环糊精主客体反应,方便易行,效率高;再引入第二个“阀门”酸酐化的环糊精β-CD- cit,构建“双阀门”药物控释载体,提高载体对药物的包封作用,降低药物循环过程中的提 前释放,提高药物利用率。
第二、本发明以介孔硅(MSN)为载体,通过将酸酐化的环糊精与二茂铁Fc进行主客体 作用,包覆在载体外面,赋予载体介孔硅(MSNs)长的循环时间。当到达癌组织附近时在弱 酸性下可实现电荷翻转,使载体表面显正电,与磷脂双分子层静电作用,促进细胞对载体的 摄取,实现一级pH敏感;引入的ZnO量子点,将ZnO量子点作为药物阀门,在癌细胞内酸性条件下水解,释放药物,实现二级pH敏感,同时具有荧光成像的作用,实现诊疗一体 化作用。
第三、本发明所述复合纳米药物载体系统构建双重pH敏感机制的同时,引入二茂铁Fc 和环糊精主客体反应,实现双氧水(H2O2)氧化敏感,能更好的实现对癌症敏感控释治疗,提 高药物释放能力。
综上所述,本发明构建一种具备“肿瘤引发靶向”能力、基于MSN/ZnO/Fc-CD-cit的复 合纳米药物载体系统,相比传统的MSN载体,该系统具备双pH敏感、H2O2氧化敏感以及 荧光成像的性质,具有更加高效的癌细胞内靶向给药能力,可以有效提高药物利用率并降低其毒副作用。
附图说明
图1中,A、B为实施例中MCM-41型介孔硅纳米粒子(MSN)的TEM电镜,C为实 施例1所得复合纳米药物载体系统DOX@MSN-ZnO-Fc-CD-cit的TEM电镜;
图2为实施例中MCM-41型介孔硅纳米粒子(MSN)的XRD图谱;
图3-1,图3-2分别为实施例中制备的氨基环糊精和酸酐化环糊精的核磁图;
图4为实施例中氨基氧化锌量子点(ZnO-NH2)的荧光和激发光谱;
图5-1、图5-2分别为空白载体MSN-N-ZnO和实施例1所得最终产物MSN-N-ZnO-Fc-CD-cit的XPS图谱;
图6为实施例1所得最终产物DOX@MSN-N-ZnO-Fc-CD-cit的电化学测试;
图7-1、图7-2分别为实施例1中所涉及各原料以及各步产物的比表面积吸脱附曲线 (BET)和孔径曲线(BJH);
图8为实施例所得最终产物DOX@MSN-ZnO-Fc-CD-cit在pH 7.4、6.5和5.0以及不同H2O2浓度下的释药曲线。
具体实施方式
为了更好地理解本发明,下面结合实施例进一步阐明本发明的内容,但本发明不仅仅局 限于下面的实施例。
下述实施例中涉及到的MCM-41型介孔硅纳米粒子(MSN)、氨基功能化MCM-41型 介孔硅纳米粒子(MSN-NH2)、羧基功能化MCM-41型介孔硅纳米粒子(MSN-COOH)、氨基 化的环糊精β-CD-NH2、氧化锌量子点(ZnO QDs)可以采用如下方法制备,也可以采用其他 方法制备。
1.制备MCM-41型介孔硅纳米粒子(MSN)
MSN的制备步骤如下:先将NaOH(0.28g)与CTAB(1g)溶解在480mL二次水中并 升温至80℃,然后将TEOS(5mL)缓慢滴加至体系中,滴完后继续搅拌2h产生白色沉 淀物。反应结束后将产物离心(9500r/min×10min)出来并用二次水和甲醇多次洗涤,50 度真空干燥后便得到包含模板CTAB的MSN(CTAB@MSN)。为了去除模板CTAB,需将 得到的CTAB@MSN(0.5g)在包含有9mL浓盐酸的甲醇(160mL)中回流48h,然后用 二次水和甲醇多次洗涤离心,50℃真空干燥后得到MSN。
如图2所示,从小角X射线衍射图谱可以看出,此MSN孔道呈六方型排列,具有三个特征小角衍射峰分别对应(100),(110)与(200)晶面的布拉格衍射峰。
2.制备氨基功能化MCM-41型介孔硅纳米粒子(MSN-NH2)
先将1.0gCTAB@MSN分散在110mL甲醇中,再加入5mL 3-氨基丙基三乙氧基硅烷(3-aminopropyltriethoxysilane,APTES)常温反应24h,甲醇充分洗涤离心后在50度下真空 干燥24h便可得到CTAB@MSN-NH2。类似的,为了去除模板CTAB,需将得到的 CTAB@MSN-NH2(0.8g)在包含有9mL浓盐酸的甲醇(160mL)中回流48h,然后用二次 水和甲醇多次洗涤,50度真空干燥24h后得到MSN-NH2。
3.制备羧基功能化MCM-41型介孔硅纳米粒子(MSN-COOH)
准确称取1.00g MSN-NH2分散在150mL重蒸过的DMSO中,超声分散均匀。然后将3.00g三乙胺和3.03g丁二酸酐逐滴滴加加入,反应于35℃搅拌下进行48h。固体产物离 心(9500r/min×10min)并用甲醇和去离子水清洗数次,冻干后得到MSN-COOH。
4.制备氨基化的环糊精β-CD-NH2
β-CD-NH2的制备是分两步:环糊精酰氯化(OTS化)、氨基化。合成p-甲苯磺酰基-β-环糊精的步骤如下:将β-环糊精称取25g悬浮于300ml浓度为0.4mol/L NaOH溶液中。在 0℃冰水浴下缓慢加入18g TsCl,搅拌45min后将沉淀过滤,滤液用稀盐酸滴定,在pH约为8 时出现沉淀,调至pH=5.98,浑浊液至于冰箱冷藏过夜,次日抽滤将沉淀用80℃去离子水重结晶再抽滤,产物在80℃下真空干燥30h。
将p-甲苯磺酰基-β-环糊精氨基化的步骤如下:10g TsO溶解在60ml无水乙二胺中,在 80℃下通入N2回流24h后,用丙酮沉淀一天后用有机漏斗过滤,再用丙酮沉淀重复2次后 真空干燥48h,得到氨基化的环糊精β-CD-NH2。
5、制备氧化锌量子点(ZnO QDs)
880mg,(4.0mmol)醋酸锌和88mg,(0.4mmol)的醋酸镁溶解在60ml热的乙醇中剧烈搅 拌,将200mg(5.0mmol)的氢氧化钠(NaOH)溶解在20ml冷的乙醇中,NaOH溶液迅速加到溶有醋酸锌和醋酸镁的乙醇溶液中,反应6h后,用己烷沉淀得到ZnO(ZnO QDs)。
下述实施例中,步骤1和步骤4均在避光条件下反应。
实施例1
一种复合纳米药物载体系统,包括如下步骤:
1.制备氨基化氧化锌量子点(ZnO-NH2QDs)
将ZnO QDs分散在20ml无水N’N-二甲基甲酰胺(DMF)中,加入100ul三氨丙基三乙氧 基硅烷(APTES),在120度下反应20min后,用DMF离心清洗几次,50度真空干燥得到白 色ZnO-NH2QDs。
2.制备氧化锌量子点封堵的药物载体DOX@MSN-N-ZnO
0.2g的MSN-COOH分散在50ml二氯甲烷中,加入50mg阿霉素(DOX),在常温避光下搅拌24h后,加入8.4g DCC、0.64g DMAP常温活化反应8h后,加入0.5g ZnO-NH2QDs反 应48h后甲醇洗两次,二次水洗两次后,冻干得到DOX@MSN-N-ZnO。
3.制备酸酐化的环糊精β-CD-cit
取1gβ-CD-NH2,溶解在100ml去离子水中,加入3g的二甲基马来酸酐,用2mol/L的NaOH溶液调节pH到8-9之间,40度下搅拌48h后,透析3d后冻干,得到酸酐化的环糊 精β-CD-cit。
4.制备β-CD-cit封装的载药系统(DOX@MSN-ZnO-Fc-CD-cit)
取0.2g二茂铁甲酸(Fc-COOH)分散在50ml二氯甲烷中,加入8.4g DCC、0.64g DMAP常温活化反应8h后,将0.200g DOX@MSN-N-ZnO分散在10ml二氯甲烷中,加入到二茂铁 甲酸溶液中,搅拌24h后,用甲醇和去离子水各清洗2次,50度下烘干得到DOX@MSN-N- ZnO-Fc;取0.1g DOX@MSN-N-ZnO-Fc分散在去离子水中,在加入0.2gβ-CD-cit冰水浴中 反应24h后,用pH=7.4PBS洗3次,水洗1次,50℃下烘干,即得到载药后的 DOX@MSN-ZnO-Fc-CD-cit。
如图1所示,MSN具有介孔结构,尺寸在100-300nm范围内;而最终产物载药系统(DOX@MSN-ZnO-Fc-CD-cit)介孔结构消失。
如图2所示,为MSN的小角XRD曲线,可以看出有(100)、(200)、(110)峰,进而 得知MSN为六方型结构,与TEM观测相符。
如图3所示,由核磁分析可知,氨基环糊精和酸酐化的环糊精均合成成功。
如图4所示,由荧光分光光度计曲线可知,氨基化ZnO量子点的激发光谱大约为340nm,发射光谱为540nm,并且荧光强度较大,具有荧光成像的潜力。
如图5所示,由元素分析曲线可知,空白载体MSN-N-ZnO含有很强的Zn 2p3能带以及实施例1所得最终产物MSN-N-ZnO-Fc-CD-cit中含有Zn 2p3和Fe 2p能带,可以定性的 说明合成成功。
如图6所示,最终产物DOX@MSN-N-ZnO-Fc-CD-cit的电化学测试,通过C-V循环曲线可以看出修饰上Fc-COOH后,DOX@MSN-N-ZnO-Fc-CD-cit具有良好的氧化还原循环性 能。
如图7为实施例1中所涉及各原料以及各步产物比表面积吸脱附曲线(BET)和孔径曲 线(BJH);可以看出随着对载体的修饰,载体的比表面积和孔径逐渐降低,说明载体表面被逐渐修饰成功,最后对MSN进行了封堵。
图8为实施例所得最终产物DOX@MSN-ZnO-Fc-CD-cit在pH 7.4、6.5和5.0以及不同H2O2浓度下的释药曲线,可知:在pH 7.4、6.5条件下120h后仅有不超过20%的药物释 放,然而在pH 5.0下在120小时内接近90%的药物释放,说明合成的最终产物DOX@MSN- ZnO-Fc-CD-cit具有很好的生理环境下的药物保护作用,进入细胞后具有良好的酸性条件下 释药的性能;同时相比有无H2O2存在时同一pH条件下的释药量可知,当存在H2O2时,药 物可以更好的释放,间接的证明了,Fc具有H2O2敏感性,可以被氧化后脱去环糊精后,从 而脱去外层阀门,帮助细胞内释药。
空白对照例
空白载体的制备过程与实施例1的区别在于:未加入阿霉素DOX。
实施例2
一种复合纳米药物载体系统,包括如下步骤:
1.制备氨基化氧化锌量子点(ZnO-NH2QDs)
将ZnO QDs分散在20ml无水N’N-二甲基甲酰胺(DMF)中,加入100ul三氨丙基三乙氧 基硅烷(APTES),在120度下反应20min后,用DMF离心清洗几次,50度真空干燥得到白 色ZnO-NH2QDs。
2.制备氧化锌量子点封堵的药物载体DOX@MSN-N-ZnO
0.2g的MSN-COOH分散在50ml二氯甲烷中,加入100mg阿霉素(DOX),在常温避光下搅拌24h后,加入8.4g DCC、0.64g DMAP常温活化反应8h后,加入0.5g ZnO-NH2QDs反 应48h后甲醇洗两次,二次水洗两次后,冻干得到DOX@MSN-N-ZnO。
3.制备酸酐化的环糊精β-CD-cit
取1gβ-CD-NH2,溶解在100ml去离子水中,加入3g的二甲基马来酸酐,用2mol/L的NaOH溶液调节pH到8-9之间,40度下搅拌48h后,透析3d后冻干,得到酸酐化的环糊 精β-CD-cit。
4.制备β-CD-cit封装的载药系统(DOX@MSN-ZnO-Fc-CD-cit)
取0.2g二茂铁甲酸(Fc-COOH)分散在50ml二氯甲烷中,加入8.4g DCC、0.64g DMAP常温活化反应8h后,将0.200g DOX@MSN-N-ZnO分散在10ml二氯甲烷中,加入到二茂铁 甲酸溶液中,搅拌24h后,用甲醇和去离子水各清洗2次,50度下烘干得到DOX@MSN-N- ZnO-Fc;取0.1g DOX@MSN-N-ZnO-Fc分散在去离子水中,在加入0.1gβ-CD-cit冰水浴中 反应24h后,用pH=7.4PBS洗3次,水洗1次,50℃下烘干,即得到载药后的 DOX@MSN-ZnO-Fc-CD-cit。
实施例3
一种复合纳米药物载体系统,包括如下步骤:
1.制备氨基化氧化锌量子点(ZnO-NH2QDs)
将ZnO QDs分散在20ml无水N’N-二甲基甲酰胺(DMF)中,加入100ul三氨丙基三乙氧 基硅烷(APTES),在120度下反应20min后,用DMF离心清洗几次,50度真空干燥得到白 色ZnO-NH2QDs。
2.制备氧化锌量子点封堵的药物载体DOX@MSN-N-ZnO
0.2g的MSN-COOH分散在50ml二氯甲烷中,加入50mg阿霉素(DOX),在常温避光下搅拌24h后,加入8.4g DCC、0.64g DMAP常温活化反应8h后,加入0.2g ZnO-NH2QDs反 应48h后甲醇洗两次,二次水洗两次后,冻干得到DOX@MSN-N-ZnO。
3.制备酸酐化的环糊精β-CD-cit
取1gβ-CD-NH2,溶解在100ml去离子水中,加入3g的二甲基马来酸酐,用2mol/L的NaOH溶液调节pH到8-9之间,40度下搅拌48h后,透析3d后冻干,得到酸酐化的环糊 精β-CD-cit。
4.制备β-CD-cit封装的载药系统(DOX@MSN-ZnO-Fc-CD-cit)
取0.2g二茂铁甲酸(Fc-COOH)分散在50ml二氯甲烷中,加入8.4g DCC、0.64g DMAP常温活化反应8h后,将0.200g DOX@MSN-N-ZnO分散在10ml二氯甲烷中,加入到二茂铁 甲酸溶液中,搅拌24h后,用甲醇和去离子水各清洗2次,50度下烘干得到DOX@MSN-N- ZnO-Fc;取0.1g DOX@MSN-N-ZnO-Fc分散在去离子水中,在加入0.1gβ-CD-cit冰水浴中 反应24h后,用pH=7.4PBS洗3次,水洗1次,50℃下烘干,即得到载药后的 DOX@MSN-ZnO-Fc-CD-cit。
以上所述仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在 不脱离本发明创造构思的前提下,还可以做出若干改进和变换,这些都属于本发明的保护范 围。
Claims (10)
1.基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,其特征在于它以介孔硅纳米粒子为载体,负载药物后,采用氨基化氧化锌量子点进行封堵,得到氧化锌量子点封堵的药物载体;接着,所得氧化锌量子点封堵的药物载体通过化学键连接二茂铁甲酸后,再与酸酐化的环糊精发生主客体反应进行二次封堵,得到基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体。
2.根据权利要求1所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,其特征在于药物主要包括阿霉素、喜树碱、紫杉醇。
3.根据权利要求1所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,其特征在于所述氨基化氧化锌量子点的制备方法如下:将氧化锌量子点分散在无水N’N-二甲基甲酰胺中,加入三氨丙基三乙氧基硅烷,在110-130℃下反应10-30min后,清洗并真空干燥后,得到白色氨基化氧化锌量子点。
4.根据权利要求1所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体,其特征在于所述酸酐化的环糊精的制备方法为:将氨基化的环糊精溶解在去离子水中,加入二甲基马来酸酐后调节体系pH 到8-9之间,30-50℃下搅拌40-55h后,透析2-4天后冻干,得到酸酐化的环糊精。
5.一种基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于包括如下步骤:
步骤1:制备氧化锌量子点封堵的阿霉素介孔硅载体
将羧基功能化MCM-41 型介孔硅纳米粒子作为载体分散在溶剂二氯甲烷中, 然后加入药物阿霉素, 在常温下避光搅拌20-28h后,再加入N,N-二环己基碳二亚胺、4-二甲氨基吡啶常温活化反应6-12h后,接着加入氨基化氧化锌量子点反应40-56h后,经洗涤、冻干得到搭载阿霉素氧化锌封堵的介孔硅基载体;
步骤2:制备环糊精封装的介孔硅载药系统
2-1、将二茂铁甲酸分散在溶剂二氯甲烷中,加入N,N-二环己基碳二亚胺、4-二甲氨基吡啶常温活化反应6-12h;
2-2、将步骤1所得搭载阿霉素氧化锌封堵的介孔硅基载体分散在溶剂二氯甲烷中,加入到步骤2-1所得溶液中搅拌20-28h,清洗烘干后得到二茂铁甲酸修饰的搭载阿霉素氧化锌封堵的介孔硅基载体;
2-3、将步骤2-2所得产物分散在去离子水中,加入酸酐化的环糊精在冰水浴中反应20-28h后,清洗烘干,即得到酸酐化环糊精保护的介孔硅基药物载体,即基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体。
6.根据权利要求5所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于所述步骤1中,羧基功能化MCM-41 型介孔硅纳米粒子与阿霉素的质量比在4:1-2:1之间、氨基化氧化锌量子点的质量比为羧基功能化MCM-41型介孔硅纳米粒子的1-3倍。
7.根据权利要求5所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于所述步骤1中,溶剂二氯甲烷保证载体浓度在1-10mg/ml;4-二甲氨基吡啶与N,N-二环己基碳二亚胺摩尔比为1:5-1:10之间。
8.根据权利要求5所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于所述步骤2-1中,4-二甲氨基吡啶与N,N-二环己基碳二亚胺的摩尔比在1:5-1:10之间,且4-甲氨基吡啶与二茂铁甲酸的摩尔比为5:1-10:1。
9.据权利要求5所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于所述步骤2中,步骤1所得载阿霉素氧化锌封堵的介孔硅基载体与二茂铁甲酸的质量比在1:1-1:2之间。
10.据权利要求5所述的基于介孔硅/环糊精/氧化锌量子点构建的“双阀门”多刺激响应型药物载体的制备方法,其特征在于步骤2-2中二茂铁甲酸修饰的搭载阿霉素氧化锌封堵的介孔硅基载体与酸酐化的环糊精的质量比在1:1-1:2之间。
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