CN105802106B - 一种温度、uv和还原剂三重响应的超分子纳米聚集体的制备方法 - Google Patents
一种温度、uv和还原剂三重响应的超分子纳米聚集体的制备方法 Download PDFInfo
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Abstract
本发明涉及一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法,以β‑环糊精修饰的温敏性共聚物(β‑CD‑P(MEO2MA‑co‑OEGMA))为主体分子,以端基为偶氮苯的两亲性嵌段聚合物(Azo‑PCL‑SS‑PEG)为客体分子,通过主‑客体静电相互作用构筑超分子组装体。用β‑环糊精的磺化和溴化产物引发ATRP反应得到主体分子;以扩链的对羟基偶氮苯开环己内酯,再通过两步酯化反应得到客体分子。分别将主客体分子溶于水中,均匀混合后得到超分子自组装胶束溶液。通过对体系施加外界刺激,胶束的形态、大小可以发生可逆且可控转变。本发明制得的超分子聚集体在药物负载与可控释放、生物智能开关、纳米智能反应器等领域有广阔的应用前景。
Description
技术领域
本发明属于高分子材料和生物医学工程领域,尤其是纳米超分子材料技术领域,具体涉及一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法。
背景技术
响应性两亲高分子的自组装行为近年来越来越受到关注。这种类型的高分子具备的一个重要性能就是,当外界环境发生变化时,高分子的化学结构会发生改变,其组装体的形态也随之发生变化,常见的组装形态有囊泡、胶束、管状、纤维状、棍状等。因此,基于响应性两亲分子的智能纳米反应器,若能在外界刺激下可逆地打开与关闭,可控地运载和释放药物,将会为药物的靶向运输带来新的应用前景。参见:1)Yan, X.; Wang, F.; Zheng,B.; Huang, F. Stimuli-Responsive Supramolecular Polymeric Materials. Chem.Soc. Rev. 2012, 41 (18), 6042–6065; 2)Ma, X.; Tian, H. Stimuli-ResponsiveSupramolecular Polymers in Aqueous Solution. Acc. Chem. Res. 2014, 47 (7),1971–1981; 3) Bajpai, A. K.; Shukla, S. K.; Bhanu, S.; Kankane, S. ResponsivePolymers in Controlled Drug Delivery. Progress in Polymer Science 2008, 33(11), 1088–1118。常见的外界刺激包括:温度、pH、光、电场、磁场、氧化剂、还原剂等,这为响应性两亲分子的应用提供了多种刺激-应答的方式。
通过主客体间的静电相互作用发生嵌套的超分子化学,可以设计和合成形态更为复杂、功能更为多样的不同拓扑结构的超分子聚集体,为两亲性嵌段共聚物的自组装打开了一扇新的大门。目前,常见的超分子体系是基于环糊精、葫芦脲、冠醚、杯芳烃为主体而构筑的。环境输入的刺激信号可以导致高分子链段的组装或解组装以及超分子体系的嵌套或解嵌套,从而改变聚集体的形态和尺寸,达到可逆且可控的行为变化。参见:1) Yuan, T.;Dong, J.; Han, G.; Wang, G. Polymer Nanoparticles Self-Assembled from Photo-,pH- and Thermo-Responsive Azobenzene-Functionalized PDMAEMA. RSC Advances2016, 6, 10904–10911; 2) Li, Y.; Qian, Y.; Liu, T.; Zhang, G.; Hu, J.; Liu,S. Asymmetrically Functionalized β-Cyclodextrin-Based Star Copolymers forIntegrated Gene Delivery and Magnetic Resonance Imaging Contrast Enhancement.Polym. Chem. 2014, 5 (5), 1743–1750; 3) Yuan, W.; Guo, W. Ultraviolet Light-Breakable and Tunable Thermoresponsive Amphiphilic Block Copolymer: FromSelf-Assembly, Disassembly to Re-Self-Assembly. Polym. Chem. 2014, 5 (14),4259–4259。
尽管现在对具有刺激响应性的β-环糊精超分子组装体的研究报道较多,但大都仅限于一种或者两种外界刺激,且可控性较差,达不到药物精确负载和释放的要求。本发明制得的超分子聚集体具有良好外界刺激响应性,包括温度、UV和还原剂三重响应刺激。并且超分子聚集体能够在外界刺激条件下发生可逆且可控的形态和尺寸变化,具备良好的实验可重复性,使其在药物负载与可控释放、生物智能开关、纳米智能反应器、紫外光探测器等领域具有广泛的应用前景。
发明内容
本发明的目的在于提供一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法。
本发明的目的是通过原子转移自由基聚合(ATRP)、开环聚合(ROP)、点击化学(click chemistry)以及酯化反应合成具有温度和还原剂响应性的主客体嵌段共聚物(β-CD-P(MEO2MA-co-OEGMA)和Azo-PCL-SS-PEG),再通过主客体间的超分子作用,制备温度、UV和还原剂三重响应的超分子纳米聚集体。具体步骤如下:
(1)主体分子β-CD-P(MEO2MA-co-OEGMA)的制备
用过量的对甲苯磺酰氯在溶剂A中对β-环糊精改性,通过与过量的叠氮化钠反应,得到β-CD-N3,再通过与过量溴代异丁酸丙炔酯的点击化学得到端基为溴的β-CD-Br。最后在溶剂B中,按β-CD-Br上溴原子摩尔数的10~150倍的量加入2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯(MEO2MA)、寡聚乙二醇甲醚甲基丙烯酸酯(OEGMA)单体(MEO2MA与OEGMA的摩尔比为10:1~10:2),加入催化剂C,体系在氩气或氮气保护下反应,反应温度为65oC,反应时间为24小时,经沉淀剂D沉淀、烘干,得到具有温度响应性的主体分子β-CD-P(MEO2MA-co-OEGMA)。其分子结构如下:
其中:j表示聚2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯(MEO2MA)的聚合度,k表示聚寡聚乙二醇甲醚甲基丙烯酸酯(OEGMA)的聚合度。
(2)客体分子Azo-PCL-SS-PEG的制备
首先用6-氯-1-己醇扩链的对羟基偶氮苯和己内酯按1:20~1:60的投料比,在辛酸亚锡作催化剂,120oC反应温度下进行开环聚合,得到Azo-PCL-OH。再在溶剂B中,加入过量1~3倍的3,3’-硫代二丙酸,在催化剂E作用下进行酯化反应,反应温度为45oC,反应时间为24小时,过滤,在沉淀剂D中沉淀、干燥,得到Azo-PCL-SS-OH。最后在溶剂B中,加入相同摩尔数的分子量为5000的聚乙二醇单甲醚,在催化剂E作用下进行酯化反应,反应温度为45oC,反应时间为24小时,过滤、透析,最后用冻干机除去水分至恒重,得到具有氧化还原响应性的客体分子Azo-PCL-SS-PEG。其分子结构如下:
其中:n表示聚己内酯的聚合度,m表示聚乙二醇单甲醚的聚合度。
(3)β-CD-P(MEO2MA-co-OEGMA)与Azo-PCL-SS-PEG超分子聚集体的制备
分别称取β-CD-P(MEO2MA-co-OEGMA)和Azo-PCL-SS-PEG质量为94mg和22.2mg,溶解于10mL溶剂B中,超声30分钟,再用微量注射器将5mL的去离子加入上述溶液,持续时间为5小时。再在去离子水中透析,定容体积为30mL。
本发明中,所述溶剂A为500mL的浓度为0.4mol/L的氢氧化钠溶液。
本发明中,所述溶剂B为四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或苯甲醚中的一种或几种。
本发明中,所述催化剂C为溴化亚铜/联吡啶、氯化亚铜/联吡啶、溴化亚铜/五甲基二乙烯基三胺、氯化亚铜/五甲基二乙烯基三胺、溴化亚铜/三(2-甲氨基乙基)胺、氯化亚铜/三(2-甲氨基乙基)胺、溴化亚铜/六甲基三亚乙基四胺、氯化亚铜/六甲基三亚乙基四胺、溴化亚铜/2-吡啶甲醛缩正丙胺或氯化亚铜/2-吡啶甲醛缩正丙胺中的一种或几种。
本发明中,所述沉淀剂D为甲醇、乙醇、异丙醇、环己烷、正己烷或乙醚中的一种或几种。
本发明中,所述催化剂E为二环己基碳酰亚胺(DCC)和4-二甲氨基吡啶(DMAP)。
通过红外光谱仪、核磁共振仪、紫外分光光度计、荧光分光光度计等表征各中间产物和最终产物的结构和性能,采用透射电子显微镜、动态激光光散射表征超分子聚集体在外界刺激前后的形态和粒径大小。
附图说明
图1:(a)β-CD-Br、(b)β-CD-P(MEO2MA-co-OEGMA)、(c)Azo-PCL-SS-OH和(d)Azo-PCL-SS-PEG的1H-NMR核磁共振谱图。
图2:主体分子β-CD-P(MEO2MA-co-OEGMA)和(c)客体分子Azo-PCL-SS-PEG组成的超分子聚集体在(a)紫外光照射后、(b)可见光照射后和(c)紫外-可见光循环照射后的紫外-可见光吸收光谱图。
图3:主体分子前驱体(a)β-CD、(b)β-CD-OTs、(c)β-CD-N3和(d)β-CD-Br的FT-IR谱图。
图4:客体分子Azo-PCL-SS-PEG的临界胶束浓度(CMC)的荧光分光光度计谱图。
图5:超分子聚集体在外界刺激(温度、紫外光和还原剂)的作用下的形态变化示意图。
图6:超分子聚集体(a)未施加刺激、(b)紫外光刺激下和(c)还原剂刺激下的形态变化TEM图。
图7:超分子聚集体(a)在紫外光和还原剂刺激下和(b)不同温度下的粒径变化DLS图。
具体实施方式
下面通过实施例进一步说明本发明。
实施例1:
具体步骤如下:
(1)对甲苯磺酰氯改性β-环糊精
称取称取β-环糊精50g,溶解于500mL的浓度为0.4mol/L的氢氧化钠溶液中,将溶液置于冰水浴中剧烈搅拌,缓慢加入对甲苯磺酰氯35g,有白色不溶物生成。混合物在5oC下搅拌30分钟,抽滤得清澈滤液。在搅拌下,用盐酸加入至上述溶液中,直至生成白色沉淀,继续搅拌1小时,抽滤,水洗三次。所得白色沉淀在60oC烘箱中烘干。
(2)β-CD-N3的合成
取上一步所得产物15g溶解于水中,加热至80oC,在此溶液中加入叠氮化钠溶液,升高温度至105oC,搅拌6小时。随后在冰的丙酮溶液中沉淀,得到白色固体,抽滤,在60oC烘箱中烘干。
(3)β-CD-Br的合成
称取6.02gβ-CD-N3,溶于DMF,加入溴代异丁酸丙炔酯2.07g,再加入催化剂氯化亚铜(738.09mg)/五甲基二乙烯基三胺(304.47mg),体系经抽真空-充氩气过程三次,在氩气保护下于50oC下反应18小时。产物在冷冻的乙纯中沉淀,过滤后放入真空烘箱,室温下干燥至恒重。
(4)β-CD-P(MEO2MA-co-OEGMA)的合成
称取0.6gβ-CD-Br,溶于N,N-二甲基甲酰胺,加入2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯7.38g、寡聚乙二醇甲醚甲基丙烯酸酯甲基丙烯酸偶氮苯氧己基酯1.62g,再加入催化剂溴化亚铜(63mg)/六甲基三亚乙基四胺(93mg),体系经抽真空-充氩气过程三次,在氩气保护下于70oC下反应12小时。产物通过中性氧化铝柱除去催化剂,然后在冷冻的正己烷中沉淀,过滤后放入真空烘箱,室温下干燥至恒重。
(5)Azo-PCL-OH的合成
称取用6-氯-1-己醇扩链的对羟基偶氮苯0.76g,依次加入己内酯11.635g,辛酸亚锡125µL,体系经抽真空-充氩气过程三次,在氩气保护下于120oC下反应24小时。停止反应,加入适量二氯甲烷溶解产物,在冷冻的甲醇中沉淀,过滤后放入真空烘箱,室温下干燥至恒重。
(6)Azo-PCL-SS-OH的合成
取上一步产物5.2g,溶解于20mL四氢呋喃溶剂中,加入3,3’-硫代二丙酸,加入催化剂二环己基碳酰亚胺0.7g和4-二甲氨基吡啶0.2g,反应温度为45oC,反应时间为24小时,过滤,在冰甲醇中沉淀,抽滤后放入真空烘箱,室温下干燥至恒重。
(7)Azo-PCL-SS-PEG的合成
取Azo-PCL-SS-OH 1.3g,溶解于二氯甲烷溶剂中,加入分子量为5000的聚乙二醇单甲醚6.4g,加入催化剂二环己基碳酰亚胺0.6g和4-二甲氨基吡啶1.22g,反应温度为45oC,反应时间为24小时,过滤除去不溶物,在去离子水中透析3天,最后用冻干机除去水分至恒重。
(8)β-CD-P(MEO2MA-co-OEGMA)与Azo-PCL-SS-PEG超分子聚集体的制备
分别称取β-CD-P(MEO2MA-co-OEGMA)和Azo-PCL-SS-PEG质量为94mg和22.2mg,溶解于10mL溶剂N,N-二甲基甲酰胺中,超声30分钟,再用微量注射器将5mL的去离子加入上述溶液,持续时间为5小时。溶液置于去离子水中透析,定容体积为30mL,用冻干机除去水分至恒重。
通过红外光谱仪、核磁共振仪、紫外分光光度计、荧光分光光度计等表征各中间产物和最终产物的结构和性能,采用透射电子显微镜、动态激光光散射表征超分子聚集在外界刺激前后的形态和粒径大小。实验结果表明超分子聚集体能够在外界刺激条件下发生可逆且可控的形态和尺寸变化,具备良好的实验可重复性,使其在药物负载与可控释放、生物智能开关、纳米智能反应器、紫外光探测器等领域具有广泛的应用前景。
(9)实验结果分析
图1为使用核磁共振仪表征的(a)β-CD-Br、(b)β-CD-P(MEO2MA-co-OEGMA)、(c)Azo-PCL-SS-OH和(d)Azo-PCL-SS-PEG的1H-NMR谱图。图中表明:各聚合物的关键基团中氢的化学位移均已在图中标示出,成功地合成了各步骤的产物。
图2为主客体分子超分子作用的紫外-可见光吸收光谱图和循环照射图。图中表明:如图(a)所示,当给与体系365nm紫外光照射后,随着照射时间的延长,体系在355nm的吸收值逐渐减小,在430nm的吸收值逐渐增大,这是由于偶氮苯由反式结构转变为顺式结构,使其从β-环糊精内腔中脱离;图(b)为体系在450nm可见光照射后体系的光吸收谱图,为上述实验的可逆过程;图(c)为紫外-可见光循环照射后的紫外-可见光吸收光谱图,为表征主客体分子组成的超分子聚集体的可逆紫外光响应性,可以看出体系具有良好的可逆性和重复性。
图3为主体分子前驱体(a)β-CD、(b)β-CD-OTs、(c)β-CD-N3和(d)β-CD-Br的红外光谱图。图中表明:β-CD-N3相比于β-CD-OTs,在2100 cm-1处出现了吸收峰,此峰为叠氮基团的特征吸收峰;当进行点击化学后,β-CD-Br相比于β-CD-N3,在1730 cm-1处出现了吸收峰,此峰为羰基的特征吸收峰,表明成功地进行了点击化学。
图4为客体分子Azo-PCL-SS-PEG的临界胶束浓度(CMC)的荧光分光光度计谱图。图中表明:客体分子的临界胶束浓度为78.6mg/L。
图5为超分子聚集体在外界刺激(温度、紫外光和还原剂)的作用下的形态变化示意图。图中表明:当给予体系紫外光照射后,以偶氮苯为端基的客体分子从以β-环糊精为端基的主体分子内腔中脱离,导致聚集体的尺寸减小;当环境温度升高时,由于主体分子中的P(MEO2MA-co-OEGMA)链段具有温度响应性(最低临界溶解温度LCST),链段逐渐收缩,导致聚集体的尺寸逐渐减小;当在体系中加入还原剂二硫苏糖醇(DTT)后,导致客体分子Azo-PCL-SS-PEG中连接PCL和PEG嵌段的二硫键的断裂,从而使聚集体的尺寸减小。
图6为超分子聚集体(a)未施加刺激、(b)紫外光刺激下和(c)还原剂刺激下的形态变化TEM图。图中表明:当经过体系紫外光照射和加入还原剂二硫苏糖醇(DTT)后,聚集体的尺寸均减小。
图7为超分子聚集体(a)在紫外光和还原剂刺激下和(b)不同温度下的粒径变化DLS图。图中表明:如图(a)所示,在未给予外界刺激下,聚集体的粒径约为80nm;当给予体系紫外光照射后,聚集体的尺寸减小到60nm左右;当在体系中加入还原剂二硫苏糖醇后,二硫键的断裂导致聚集体尺寸分布变宽,粒径差距增大;如图(b)所示,聚集体粒径随着环境温度升高而逐渐减小,在LCST附近,聚集体的尺寸减小速率明显增大,表现出良好的温度响应性。
Claims (3)
1.一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法,其特征在于:构筑单元以β-环糊精修饰的温敏性共聚物β-CD-P(MEO2MA-co-OEGMA)为主体分子,以端基为偶氮苯的两亲性嵌段聚合物Azo-PCL-SS-PEG为客体分子,通过主体分子-客体分子静电相互作用构筑超分子纳米聚集体,其具体步骤如下:
(1)主体分子β-CD-P(MEO2MA-co-OEGMA)的制备
用过量的对甲苯磺酰氯在溶剂A中对β-环糊精改性,通过与过量的叠氮化钠反应,得到β-CD-N3,再通过与过量溴代异丁酸丙炔酯的点击化学得到端基为溴的β-CD-Br,最后在溶剂B中,按β-CD-Br上溴原子摩尔数的10~150倍的量加入2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯MEO2MA、寡聚乙二醇甲醚甲基丙烯酸酯OEGMA单体,其中:MEO2MA与OEGMA的摩尔比为10:1~10:2,加入催化剂C,体系在氩气或氮气保护下反应,反应温度为65oC,反应时间为24小时,经沉淀剂D沉淀、烘干,得到具有温度响应性的主体分子β-CD-P(MEO2MA-co-OEGMA);
(2)客体分子Azo-PCL-SS-PEG的制备
首先用6-氯-1-己醇扩链的对羟基偶氮苯和己内酯按1:20~1:60的投料比,在辛酸亚锡作催化剂,120oC反应温度下进行开环聚合,得到Azo-PCL-OH,再在溶剂B中,加入过量1~3倍的3,3’-硫代二丙酸,在催化剂E作用下进行酯化反应,反应温度为45oC,反应时间为24小时,过滤,在沉淀剂D中沉淀、干燥,得到Azo-PCL-SS-OH,最后在溶剂B中,加入相同摩尔数的分子量为5000的聚乙二醇单甲醚,在催化剂E作用下进行酯化反应,反应温度为45oC,反应时间为24小时,过滤、透析,最后用冻干机除去水分至恒重,得到具有氧化还原响应性的客体分子Azo-PCL-SS-PEG;
(3)β-CD-P(MEO2MA-co-OEGMA)与Azo-PCL-SS-PEG超分子聚集体的制备
分别称取β-CD-P(MEO2MA-co-OEGMA)和Azo-PCL-SS-PEG质量为94mg和22.2mg,溶解于10mL溶剂B中,超声30分钟,再用微量注射器将5mL的去离子加入上述溶液,持续时间为5小时,溶液置于去离子水中透析,定容体积为30mL;
其中:所述溶剂A为500mL的浓度为0.4mol/L的氢氧化钠溶液;所述溶剂B为四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或苯甲醚中的一种或几种;所述催化剂C为溴化亚铜/联吡啶、氯化亚铜/联吡啶、溴化亚铜/五甲基二乙烯基三胺、氯化亚铜/五甲基二乙烯基三胺、溴化亚铜/三(2-甲氨基乙基)胺、氯化亚铜/三(2-甲氨基乙基)胺、溴化亚铜/六甲基三亚乙基四胺、氯化亚铜/六甲基三亚乙基四胺、溴化亚铜/2-吡啶甲醛缩正丙胺或氯化亚铜/2-吡啶甲醛缩正丙胺中的一种或几种;所述沉淀剂D为甲醇、乙醇、异丙醇、环己烷、正己烷或乙醚中的一种或几种;所述催化剂E为二环己基碳酰亚胺DCC和4-二甲氨基吡啶DMAP。
2.根据权利要求1所述的一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法,所制得的主体分子结构为:
其中:j表示聚2-甲基-2-丙烯酸-2-(2-甲氧基乙氧基)乙酯MEO2MA的聚合度,k表示聚寡聚乙二醇甲醚甲基丙烯酸酯OEGMA的聚合度;
表示成β-CD-P(MEO2MA-co-OEGMA)。
3.根据权利要求1所述的一种温度、UV和还原剂三重响应的超分子纳米聚集体的制备方法,所制得的客体分子结构为:
其中:n表示聚己内酯的聚合度,m表示聚乙二醇单甲醚的聚合度;
表示成Azo-PCL-SS-PEG。
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