CN107049946A - 一种pH刺激响应的两亲性线形嵌段聚合物的制备方法 - Google Patents
一种pH刺激响应的两亲性线形嵌段聚合物的制备方法 Download PDFInfo
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Abstract
本发明涉及药物化学的合成领域,具体涉及一种pH刺激响应的两亲性线形嵌段聚合物的制备方法及应用,其制备方法包括以下步骤:(1)制备基于聚乙二醇甲醚的原子自由基聚合反应(ATRP)引发剂(MPEG‑Br);(2)通过ATRP制备pH敏感性的两亲性线形聚合物(MPD);(3)通过ATRP制备PH敏感性的线性聚合物(MPD‑NH2),以引入荧光分子;(4)制备载有近红外荧光分子Cy5的两亲性线形聚合物(MPD‑Cy5)。该载药系统具有良好生物相容性,高胶束稳定性,较高药物上载量以及能实现pH调节的可控药物释放,同时,荧光分子的引入能够进行近红外成像,从而使该系统兼具治疗与成像功能。
Description
技术领域
本发明涉及一种超高pH刺激响应的两亲性线形嵌段聚合物制备方法。
背景技术
阿霉素(Doxorubicin,CAS号:23214-92-8,分子式:C27H29NO1,相对分子量:543.52)是一种抗肿瘤抗生素,可抑制RNA 和DNA的合成,对RNA的抑制作用最强,抗瘤谱较广,对多种肿瘤均有作用,属周期非特异性药物,对各种生长周期的肿瘤细胞都有杀灭作用。但特异选择性较差、药物利用率较低以及毒副作用较强等缺陷严重制约了游离药物分子的应用。因此设计合适的药物载体对提高药效及降低毒副作用具有重要意义。
通过利用肿瘤细胞内部及周围的特殊环境,刺激响应的纳米药物载体可以将药物分子靶向递送至病灶点,从而提高治疗效率,降低药物副作用。但当前的药物递送系统普遍面临上载量低,稳定性较差以及不可控释放等问题,目前能用于临床应用的载药系统并不多。因此,设计、构建集具备高药物上载量,毒副作用小和稳定性较强的 刺激响应型药物递送系统具有很强的必要性。
发明内容
针对当前药物递送系统存在的问题,本发明创造性地设计出一类pH响应且具有良好生物相容性的两亲性线形聚合物作为抗癌药物载体,有利于实现药物的可控释放,提高药物上载量。
本发明具体技术方案如下:
一种pH刺激响应的两亲性线形嵌段聚合物的制备方法,包括以下步骤:
(1)制备基于聚乙二醇甲醚(MPEG)的原子自由基聚合反应(ATRP)引发剂(MPEG-Br),其反应式如下所示:在氩气(Ar,2-10Pa)氛围下,将聚乙二醇甲醚(MPEG)溶于四氢呋喃(THF)溶液,并加入适量三乙胺(TEA),随后逐滴加入溶于四氢呋喃的2-溴代异丁酰溴(BIBB)溶液,室温避光反应24小时,用乙醚沉淀并提纯,得到所需引发剂(MPEG-Br);
(2)制备pH敏感性的两亲性线形聚合物(MPD):在氩气(Ar,2-10Pa)氛围下,将步骤(1)所得线形ATRP引发剂(MPEG-Br)、2-(二异丙基氨基)甲基丙烯酸乙酯(DPA)和溴化亚铁(CuBr)溶解到无水N,N-二甲基甲酰胺(DMF)和异丙醇的混合溶剂中,历经三次冷冻-解冻循环,之后加入配体N,N,N′,N′′,N′′-五甲基二乙烯三胺(PMDETA),再冷冻-解冻循环两次,40℃油浴条件下反应20小时后,用四氢呋喃(THF)稀释过Al2O3柱子,浓缩,用甲醇透析提纯,真空干燥获得所需产物,其反应式如下所示;
(3)制备PH敏感性的线形聚合物(MPD-NH2):在氩气(Ar,2-10Pa)氛围下,将步骤(1)所得引发剂(MPEG-Br)、2-(二异丙基氨基)甲基丙烯酸乙酯(DPA)、 2-氨乙基甲基丙烯酸酯盐酸盐(AMH)和溴化亚铁(CuBr)分散到N,N-二甲基甲酰胺(DMF)和异丙醇的混合溶剂中,冷冻-解冻循环三次,加入配体PMEDTA,再冷冻-解冻循环两次,在40℃下反应20小时后,用四氢呋喃(THF)稀释过Al2O3柱子,浓缩,用甲醇透析提纯获得所需产物,其反应式如下所示;
(4)制备载有近红外荧光分子(Cy5)的两亲性线形聚合物(MPD-Cy5):将步骤(3)制得的pH敏感性的线形聚合物(MPEG-PDPA-NH2)和N-羟基琥珀酰亚胺修饰的近红外荧光分子(NHS-Cy5)溶解在无水N,N-二甲基甲酰胺(DMF)中,室温避光反应48小时后,用甲醇透析提纯得到所需产物,其反应式如下所示;
(5)制备pH敏感性聚合物纳米胶束(MPD和MPD-DOX),包括以下步骤:在室温(25℃),将一定量步骤(2)制备的MPD溶于DMF中,搅拌条件下逐滴加入到二次水中,搅拌30min,用二次水透析得到所需纳米胶束水溶液(MPD);加入一定量阿霉素和三乙胺后,用同样的方法制备载药胶束(MPD-DOX).
进一步的,步骤(1)中MPEG、TEA与BIBB的摩尔比为1:(5~20):(10~30),需要将三者完全溶解在THF中,且MPEG需在40℃加热条件下溶解。
进一步的,步骤(2)中引发剂MPEG-Br、单体DPA、催化剂CuBr、配体PMDETA的摩尔比为1:(25~80):(1~2):(1~2.5);步骤(2)中的DMF和异丙醇的混合溶剂中的异丙醇与DMF的体积比为1:(0.5~2)。
进一步的,步骤(3)中MPEG-Br、DPA、AMH、、CuBr、PMDETA的摩尔比为1:(25~80):(4~10):(1~2):(1~2.5);步骤(3)中的DMF和异丙醇的混合溶剂中的混合溶剂中异丙醇与DMF的体积比为1:(0.5~2)。
进一步的,步骤(4)中MPEG-PDPA-NH2与NHS-Cy5的摩尔比为1:(0.3~1)。
进一步的,步骤(5)聚合物MPD、阿霉素与三乙胺的摩尔比为1:(2~10):(6~30),所制得的胶束浓度范围为0.008 mg·L-1~600 mg·L-1。
本发明的主要优点在于:
1、针对当前药物递送系统存在的问题,本发明创造性地设计出一类pH响应且具有良好生物相容性的两亲性线形聚合物作为抗癌药物载体,有利于实现药物的可控释放,提高药物上载量。
2、本项目中,载药系统兼具治疗与成像功能。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图:
图1为本发明实施例中pH响应两亲性线形聚合物(MPD,MPD-NH2和MPD-Cy5)的制备流程示意图。
图2为本发明实施例中pH响应两亲性线形聚合物(MPD和MPD-NH2)的核磁表征图。
图3为本发明实施例中pH响应两亲性线形聚合物(MPD 和MPD-DOX和)纳米胶束的TEM和DLS示意图。
图4为本发明实施例中三种不同分子量pH响应两亲性线形聚合物(MPD-DOX)胶束的药物释放结果图。
图5为本发明实施例中三种不同分子量pH响应两亲性线形聚合物(MPD-DOX和MPD)对MCF-7细胞的毒性测试图。
图6为本发明实施例中三种不同分子量pH响应两亲性线形聚合物(MPD-DOX和MPD)对HaLa细胞的毒性测试图。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1 制备pH刺激响应的两亲性线形聚合物MPD
(1)制备引发剂(MPEG-Br):在氩气(2-10Pa)氛围下,将5.000g聚乙二醇甲醚(MPEG)溶于30mL四氢呋喃溶液,并加入1.4mL三乙胺,加热搅拌使固体溶解,随后逐滴加入溶于10mL四氢呋喃的1.0mL 2-溴代异丁酰溴(BIBB)溶液,室温(25℃)避光反应24小时,过滤得滤液,浓缩后用乙醚沉淀并提纯,得到所需引发剂(MPEG-Br)。
(2)制备聚合物(MPD):在室温(25℃)氩气(2-10Pa)氛围下,将步骤(1)所得引发剂MPEG-Br(500.0mg)、2-(二异丙基氨基)甲基丙烯酸乙酯(1.075g)、溴化亚铁(14.4mg)溶解到无水N,N-二甲基甲酰胺(3.0mL)和异丙醇(3.0mL)的混合溶剂中,历经三次冷冻-解冻循环,之后加入配体N,N,N′,N′′,N′′-五甲基二乙烯三胺(21.0uL),再冷冻-解冻循环两次,40℃油浴条件下反应20小时后,用四氢呋喃稀释过Al2O3柱子,浓缩,用甲醇透析提纯,真空干燥获得所需产物。图2 中3.83, 2.98 和 2.61 ppm的位置对应DPA片段的特征峰,3.38和3.65是MPEG片段的特征峰,表明成功合成MPEG-PDPA。
(3)制备聚合物(MPD-NH2):在室温(25℃)氩气(2-10Pa)氛围下,将步骤(1)所得引发剂MPEG-Br(250.0mg)、2-(二异丙基氨基)甲基丙烯酸乙酯(537.5mg)、 2-氨乙基甲基丙烯酸酯盐酸盐(43.0mg)、溴化亚铁(7.2mg)分散到N,N-二甲基甲酰胺(3.0mL)和异丙醇(3.0mL)的混合溶剂中,冷冻-解冻循环三次,加入22.0uL配体PMEDTA,再冷冻-解冻循环两次,在40℃油浴条件下反应20小时后,用四氢呋喃稀释过Al2O3柱子,浓缩,用甲醇透析提纯获得所需产物,如图2,MPEG-PDPA-NH2的核磁图中 3.54和 4.07 ppm处的峰表明了AMH嵌段成功接入MPEG-PDPA聚合物,即MPEG-PDPA-NH2 成功合成。
(4)制备载有近红外荧光分子(Cy5)的聚合物(MPD-Cy5):将步骤(3)制得的线形聚合物MPEG-PDPA-NH2(50.0mg)和N-羟基琥珀酰亚胺修饰的近红外荧光分子(3.0mg)溶解在无水N,N-二甲基甲酰胺(2.0mL)中,室温避光反应48小时后,用甲醇透析提纯得到所需产物。
(5)制备聚合物纳米胶束(MPD和MPD-DOX):室温条件下,将2.0mg DOX.HCl和10mg两亲性聚合物(MPEG-PDPA)溶于1mL DMF溶液,并加入5μL 三乙胺,搅拌均匀后逐滴加入到10mL二次水中,用二次水透析24h即可得到所需载药(MPD-DOX)胶束;不加三乙胺和阿霉素的条件下,同样的放方法制备空白胶束(MPD)。图3分别为空白胶束(MPD-2)和载药胶束(MPD-2-DOX)的TEM及DLS图,可以看出,它们的粒径都比较小,容易进入肿瘤细胞;从图4可知,在pH为5.0时,释放效果最好的MPD-2-DOX释放率达到74.5%,而pH为7.4时,MPD-2-DOX的释放率为29.8%,表明材料具有良好的pH响应特性;图5为纳米胶束对MCF-7细胞的毒性测试图;图6为纳米胶束对Hela细胞的毒性测试图,不难看出,该载药胶束对两种肿瘤细胞都有较强的杀伤能力,而空白胶束基本没有杀伤作用。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (6)
1.一种pH刺激响应的两亲性线形嵌段聚合物的制备方法,其特征在于:包括以下步骤:
(1)制备基于聚乙二醇甲醚(MPEG)的原子自由基聚合反应(ATRP)引发剂(MPEG-Br),其反应式如下所示,包含以下步骤:在氩气(2-10Pa)氛围下,将聚乙二醇甲醚(MPEG)溶于四氢呋喃(THF)溶液,并加入适量三乙胺(TEA),随后逐滴加入溶于四氢呋喃的2-溴代异丁酰溴(BIBB)溶液,室温避光反应24小时,用乙醚沉淀并提纯,得到所需引发剂(MPEG-Br):
(2)制备pH敏感性的两亲性线形聚合物(MPD),其反应式如下所示,包含以下步骤:在氩气(Ar,2-10Pa)氛围下,将步骤(1)所得线形ATRP引发剂(MPEG-Br)、2-(二异丙基氨基)甲基丙烯酸乙酯(DPA)和溴化亚铁(CuBr)溶解到无水N,N-二甲基甲酰胺(DMF)和异丙醇的混合溶剂中,历经三次冷冻-解冻循环,之后加入配体N,N,N′,N′′,N′′-五甲基二乙烯三胺(PMDETA),再冷冻-解冻循环两次,40℃油浴条件下反应20小时后,用四氢呋喃(THF)稀释过Al2O3柱子,浓缩,用甲醇透析提纯,真空干燥获得所需产物;
(3)制备PH敏感性的线形聚合物(MPD-NH2),其反应式如下所示,包含以下步骤:在氩气(Ar,2-10Pa)氛围下,将步骤(1)所得引发剂(MPEG-Br)、2-(二异丙基氨基)甲基丙烯酸乙酯(DPA)、 2-氨乙基甲基丙烯酸酯盐酸盐(AMH)和溴化亚铁(CuBr)分散到N,N-二甲基甲酰胺(DMF)和异丙醇的混合溶剂中,冷冻-解冻循环三次,加入配体PMDETA,再冷冻-解冻循环两次,在40℃下反应20小时后,用四氢呋喃(THF)稀释过Al2O3柱子,浓缩,用甲醇透析提纯获得所需产物;
(4)制备载有近红外荧光分子(Cy5)的两亲性线形聚合物(MPD-Cy5),其反应式如下所示,包含以下步骤:将步骤(3)制得的pH敏感性的线形聚合物(MPEG-PDPA-NH2)和N-羟基琥珀酰亚胺修饰的近红外荧光分子(NHS-Cy5)溶解在无水N,N-二甲基甲酰胺(DMF)中,室温避光反应48小时后,用甲醇透析提纯得到所需产物;
(5)制备pH敏感性聚合物纳米胶束(MPD和MPD-DOX),包括以下步骤:在室温(25℃),将步骤(2)制备的MPD溶于DMF溶液中,搅拌条件下逐滴加入到二次水中,搅拌30min,用二次水透析得到所需纳米胶束水溶液(MPD);加入阿霉素和三乙胺后,用同样的方法制备载药胶束(MPD-DOX)。
2.根据权利要求1所述的一种pH刺激响应的两亲性线形嵌段聚合物制备方法,其特征在于:所述步骤(1)中MPEG、TEA与BIBB的摩尔比为1:(5~20):(10~30),需要将三者完全溶解在THF中,且MPEG需在40℃加热条件下溶解。
3.根据权利要求1所述的一种pH刺激响应的两亲性线形嵌段聚合物制备方法,其特征在于:步骤(2)中引发剂MPEG-Br、单体DPA、催化剂CuBr和配体PMDETA的摩尔比为1:(25~80)、(1~2)、(1~2.5);所述步骤(2)中的DMF和异丙醇的混合溶剂中的异丙醇与DMF的体积比为1:(0.5~2)。
4.根据权利要求1所述的一种pH刺激响应的两亲性线形嵌段聚合物制备方法,其特征在于:所述步骤(3)中MPEG-Br、DPA、AMH、CuBr和PMDETA的摩尔比为1:(25~80):(4~10):(1~2):(1~2.5);所述步骤(3)中的DMF和异丙醇的混合溶剂中异丙醇与DMF的体积比为1:(0.5~2)。
5.根据权利要求1所述的一种pH刺激响应的两亲性线形嵌段聚合物制备方法,其特征在于:所述步骤(4)中MPEG-PDPA-NH2与NHS-Cy5的摩尔比为1:(0.3~1)。
6.根据权利要求1所述的一种pH刺激响应的两亲性线形嵌段聚合物制备方法,其特征在于:所述步骤(5)中聚合物MPD、阿霉素与三乙胺的摩尔比为1:(2~10):(6~30),所制得的胶束浓度范围为0.008 mg·L-1~600 mg·L-1。
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