CN114957656A - 一种兼具lcst及ucst的多刺激响应性荧光聚乙烯亚胺的制备方法 - Google Patents
一种兼具lcst及ucst的多刺激响应性荧光聚乙烯亚胺的制备方法 Download PDFInfo
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Abstract
本发明涉及一种制备兼具低临界溶解温度LCST及高临界溶解温度UCST的多刺激响应性聚乙烯亚胺的方法。该方法是以聚乙烯亚胺和多刺激响应性单体，在有机溶剂中通过aza‑Michael加成聚合制得。本发明的操作简单，生产成本和能耗较低。通过本发明方法所得聚合物，无细胞毒性，不仅对温度、pH及CO2具有刺激响应性，兼具LCST及UCST双重温度刺激响应的相变行为，并且具有簇集诱导发光性能，在药物的控释及细胞成像等领域应用前景广泛。
Description
技术领域
本发明涉及一种兼具低临界溶解温度LCST及高临界溶解温度UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，具体涉及一种通过aza-Michael加成制备的新型多刺激响应性荧光聚合物，属于智能材料、功能高分子、生物医药材料领域。
背景技术
多刺激响应性荧光聚合物(SRFP)在受到外界环境变化的影响时，其自身的物理及化学性质，尤其是荧光性质会随之发生相应的改变。鉴于这一独特的性质，SRFP已广泛应用于药物控释、细胞成像、智能检测等领域。传统制备SRFP的方法是将荧光物质通过物理及化学作用包覆或键合到刺激响应性聚合物上。这些荧光物质通常包括过渡金属离子、量子点以及共轭荧光染料等。对于这些荧光物质而言，许多缺陷是显而易见的：比如金属离子及量子点稳定性较差、具有一定的毒性；共轭有机染料易于泄露、水溶性差、且具有聚集诱导猝灭效应(ACQ)，难以在较高的浓度下进行应用。具有非传统发色团(羰基、叔氨基、酯基、酰胺基)簇集诱导发光的聚合物一般具有亲水性、无毒性、良好的生物相容性和加工性能, 已成为荧光聚合物的研究热点之一。
常见的具有低临界溶解温度(LCST)的性质温度响应性聚合物包括聚N-异丙基丙酰胺、聚N,N-二乙基丙烯酰胺、聚N-乙烯基己内酰胺等，而具有高临界溶解温度(UCST)的聚合物则包括一些两亲性聚合物。通过改变溶剂组成以及改变聚合物组分可对聚合物的相变行为从LCST到UCST进行转变，关于在水中同时具有LCST及UCST性质聚合物的研究却鲜有报道。因此，合成兼具LCST及UCST的无毒性的基于非传统发色团簇集诱导发光的多刺激响应聚合物具有重要的学术及应用价值。
发明内容
针对现有技术的不足，本发明提供一种兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的简单方法。是以聚乙烯亚胺和含α,β-不饱和羰基的多刺激响应性单体为反应单体，在有机溶剂中通过aza-Michael加成聚合制得。本发明的操作简单，生产成本和能耗较低。通过本发明方法所得聚合物，无细胞毒性，不仅对温度、pH及CO2具有刺激响应性，并且具有簇集诱导发光性能，在药物的控释及细胞成像等领域应用前景广泛。
发明详述：
1. 本发明的一种兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，技术方案如下：
将聚乙烯亚胺与含α,β-不饱和羰基的多刺激响应性单体溶解在溶剂中，在室温下进行aza-Michael加成反应，通过核磁共振检测产物中双键，直至双键特征峰完全消失；通过旋转蒸发仪除去溶剂得到粘稠状油性液体产物，即兼具低临界溶解温度LCST及高临界溶解温度UCST的多刺激响应性荧光聚乙烯亚胺；
所述含α,β-不饱和羰基的多刺激响应性单体，选自下列之一：N-异丙基丙烯酰胺、N, N-二甲基丙烯酰胺、N, N-二甲基氨乙基丙烯酸酯、N, N-二乙基氨乙基丙烯酸酯；
所述聚乙烯亚胺与含α,β-不饱和羰基的多刺激响应性单体，聚乙烯亚胺中的胺基与α,β-不饱和羰基的多刺激响应性单体中的碳碳双键的摩尔比为0.2~1.0﹕1.0；
所述兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺，典型的构造式如下：
所述聚乙烯亚胺，分子量为600 Da.、1800 Da.、10000 Da.；
所述溶剂，选自下列之一：乙醇、乙腈、二氯甲烷、三氯甲烷、丙酮、水；
所述aza-Michael加成反应，属无催化反应，反应时间1-2天；
所述多刺激响应性，包括温度响应性、pH响应性、盐浓度响应性和CO2响应性；
所述多刺激响应性荧光为聚合物簇集诱导发光；所述温度响应性，是指功能材料的低临界溶解温度在15-60 ℃范围；所述pH响应性，是指在pH在2-10内，功能材料的低临界溶解温度在20-40 ℃范围；所述CO2响应性，是指功能材料的低临界溶解温度在20-50 ℃范围。
2. 如上所述的制备方法制得的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺用于细胞成像和药物控释的应用
（1）所述的用于细胞成像的应用，步骤如下：
将Hela细胞加入含质量分数为10%胎牛血清的氨基酸葡萄糖培养基后，在体积分数5 % CO2、37 ºC环境中培养过夜。然后将细胞接种到激光共聚焦皿中，继续培养12 h。再将细胞用2 mg/mL的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺培养30 min，接着用pH为7.4的PBS缓冲溶液洗涤三次后用共聚焦显微镜进行观察并拍照。
（2）所述的用于药物控释的应用，步骤如下：
将0.2 g兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺及0.1 g 维生素C溶解在2.0 mL N,N-二甲基甲酰胺中，置于截留分子量为3000 Da 的纤维素透析袋中，采用1000mL去离子水透析2 h。
本发明的技术特点及优良效果：
本发明的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺，其技术特点是：采用aza-Michael加成为聚合反应，该反应条件温和，不受其它功能基团干扰，无需催化，可在室温下进行。采用聚乙烯亚胺为聚合单体，无细胞毒性，生物相容性高。本发明制备的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺对温度、pH及CO2具有刺激响应性，响应范围宽，响应灵敏度高，相转变过程快，对油溶性药物的增容与控释效果优异。本发明制备的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺具有较强的荧光，属于非传统的簇集诱导发光机理，细胞成像及药物控释效果良好。
本发明与现有技术相比具有如下优点：
1. 现有技术制备多刺激响应荧光聚合物时，步骤繁琐，条件苛刻，需将量子点、过渡金属纳米粒子或共轭有机发色团通过物理或化学作用连接到多刺激相应聚合物中，所加入的量子点及金属纳米粒子化学稳定性差，毒性高，加入的共轭发色团不仅易泄露、易发生聚集诱导猝灭，而且往往具有难合成、疏水性、生物相容性及加工性能差等缺陷。本发明制备的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺无需额外加入任何发光团就具有较强的荧光，毒性低、生物相容性好。
2. 现有技术制备的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺通常仅具有低临界溶解温度(LCST)或仅具有高临界溶解温度(UCST)，本发明制备的多刺激响应性荧光聚乙烯亚胺在水中兼具LCST及UCST双重相变行为，对于扩展其在药物控释、微催化智能控制体系都具有重要价值。
3. 现有技术制备的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺，如聚N-异丙基丙烯酰胺，往往具有明显的响应滞后性, 与蛋白质之间具有较强的氢键作用和吸附作用, 水解后产生一定细胞毒性的低分子胺等缺陷。本发明制备的有机硅-聚乙二醇嵌段共聚物对温度、pH及CO2具有刺激响应性，响应范围宽，响应灵敏度高，相转变过程快。
4. 本发明兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺是通过胺烯反应制得，可按预期的最低临界温度进行投料，在室温下及水溶液中进行，所用原料成本低，制备工艺简单、方法可靠、环境友好、转化率高、反应能耗低，工业化应用前景好。
附图说明
图1浓度为50.0 mg/mL的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺水溶液透光率随温度变化。
图2浓度为100.0 mg/mL的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺水溶液透光率随温度变化。
具体实施方式
下面结合具体实施例对本发明做进一步说明，但不限于此。
采用UV-Vis.进行测定兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的临界溶解温度LCST和UCST, 测定波长为560 nm，采用HAAKE温度控制系统调节体系温度范围为20-80 ℃，升温速率为2 ℃/min。20 ℃时溶液澄清透明，透光率设为100 %，指定透光率将至50%时的温度为其LCST值及UCST值。
实施例1.
将1.34 g N-异丙基丙烯酰胺与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为36.7 ℃，UCST值为65.5 ℃。
实施例2.
将1.68 g N-异丙基丙烯酰胺与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为1:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为35.4 ℃，UCST值为71.0 ℃。
实施例3.
将1.01 g N-异丙基丙烯酰胺与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为41.0 ℃，UCST值为50.3 ℃。
实施例4.
将1.34 g N-异丙基丙烯酰胺与0.86 g分子量为600 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为600 Da，其浓度为50.0 mg/mL水溶液的LCST值为42.2 ℃，UCST值为55.3 ℃。
实施例5.
将1.34 g N-异丙基丙烯酰胺与0.86 g分子量为10000 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为32.8 ℃，UCST值为68.4 ℃。
实施例6.
将1.60 g N, N-二甲基丙烯酰胺与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为41.7 ℃，UCST值为63.5 ℃。
实施例7.
将2.28 g N, N-二甲基氨乙基丙烯酸酯与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为34.4 ℃，UCST值为68.7 ℃。
实施例8.
将2.72 g N, N-二乙基氨乙基丙烯酸酯与0.86 g分子量为1800 Da.聚乙烯亚胺，双键与胺基摩尔比为0.8:1，一同溶解在20 mL无水乙醇中，室温搅拌24 h.。通过1H NMR检测产物中双键，直至双键特征峰完全消失。通过旋转蒸发仪除去乙醇得到粘稠状油性液体，即兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺。
所得兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的分子量为2000 Da，其浓度为50.0 mg/mL水溶液的LCST值为68.6 ℃，UCST值为59.8 ℃。
Claims (10)
1.一种兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，步骤如下：
将聚乙烯亚胺与含α,β-不饱和羰基的多刺激响应性单体溶解在溶剂中，在室温下进行aza-Michael加成反应，通过核磁共振检测产物中双键，直至双键特征峰完全消失；通过旋转蒸发仪除去溶剂得到粘稠状油性液体产物，即兼具低临界溶解温度LCST及高临界溶解温度UCST的多刺激响应性荧光聚乙烯亚胺；
所述含α,β-不饱和羰基的多刺激响应性单体，选自下列之一：N-异丙基丙烯酰胺、N,N-二甲基丙烯酰胺、N, N-二甲基氨乙基丙烯酸酯、N, N-二乙基氨乙基丙烯酸酯；
所述聚乙烯亚胺与含α,β-不饱和羰基的多刺激响应性单体，聚乙烯亚胺中的胺基与α,β-不饱和羰基的多刺激响应性单体中的碳碳双键的摩尔比为0.2~1.0﹕1.0；
聚乙烯亚胺与含α,β-不饱和羰基的多刺激响应性单体溶解在溶剂中，聚乙烯亚胺和含α,β-不饱和羰基的多刺激响应性单体的质量分数10 %-50 %；
所述兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺，典型的构造式如下：
如权利要求1所述的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，其特征在于，所述聚乙烯亚胺，分子量为600 Da.、1800 Da.、10000 Da.。
2.如权利要求1所述的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，其特征在于，所述溶剂，选自下列之一：乙醇、乙腈、二氯甲烷、三氯甲烷、丙酮、水。
3.如权利要求1所述的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，其特征在于，所述aza-Michael加成反应，属无催化反应，反应时间1-2天。
4.如权利要求1所述的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，其特征在于，所述多刺激响应性，包括温度响应性、pH响应性、盐浓度响应性和CO2响应性。
5.如权利要求1所述的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺的制备方法，其特征在于，所述多刺激响应性荧光为聚合物簇集诱导发光。
6.如权利要求1所述的制备方法制得的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺用于细胞成像和药物控释的应用。
7.如权利要求7所述的用于细胞成像的应用，其特征在于，步骤如下：
将Hela细胞加入含质量分数为10 %胎牛血清的氨基酸葡萄糖培养基后，在体积分数5% CO2、37 ºC环境中培养过夜。
8.然后将细胞接种到激光共聚焦皿中，继续培养12 h。
9.再将细胞用2 mg/mL的兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺培养30min，接着用pH为7.4的PBS缓冲溶液洗涤三次后用共聚焦显微镜进行观察并拍照。
10.如权利要求7所述的用于药物控释的应用，其特征在于，步骤如下：
将0.2 g兼具LCST及UCST的多刺激响应性荧光聚乙烯亚胺及0.1g 维生素C溶解在2.0mL N,N-二甲基甲酰胺中，置于截留分子量为3000 Da 的纤维素透析袋中，采用1000 mL去离子水透析2 h。
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