CN114146185A - 一种具有ros智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法 - Google Patents
一种具有ros智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有ROS智能响应的八臂聚乙二醇‑苯硼酸‑甘草酸药物递送系统及其制备方法，其特征在于，以端基为羧基的八臂聚乙二醇为骨架，采用酰胺化反应连接功能单体—3‑氨基苯硼酸，通过硼酸酯键连接疏水性药物—甘草酸，得到高载药量、多位点的药物递送系统。
Description
技术领域
本发明涉及一种具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法，属于生物医药和高分子纳米材料技术领域。
背景技术
作为甘草的主要活性成分，甘草酸具有广泛的药理作用，包括抗肿瘤作用和抗病毒作用等，但其也存在天然活性成分普遍的问题，如药物水溶性差、体内循环时间短等问题。近年来，智能响应药物递送系统被广泛应用于抗肿瘤药物递送，其高负载量和智能响应的特点大大降低了治疗的副作用，为肿瘤治疗开辟了新的方向。
同时，回顾人类的历史，病毒感染一直持续威胁着人类的健康，造成严重的经济损失和社会影响。新型冠状病毒肺炎(COVID-19)的爆发再次对人类健康和社会公共卫生安全产生了极大的威胁。近十年来，在SARS和COVID-19的治疗过程中，甘草酸都发挥了重要的作用。其主要的抗病毒机制包括：抑制病毒的附着和渗透，抑制病毒DNA 的复制和相关蛋白的表达，调节细胞因子以发挥抗炎作用等。冠状病毒主要通过刺突蛋白(S 蛋白)与人血管紧张素转化酶2(ACE2)结合进入细胞。已有研究表明，甘草酸可与S蛋白结合，阻碍其与ACE2受体蛋白的结合，进而抑制病毒感染。针对甘草酸与病毒S蛋白结合这一作用机制，将药物递送系统用于抗病毒药物递送，设计具有广谱、多作用位点的药物递送系统，将为广谱抗病毒药物的开发提供新的可能。
在上述研究的基础上，本发明以端基为羧基的八臂聚乙二醇为骨架，经酰胺化反应连接苯硼酸后，通过硼酸酯键连接甘草酸，得到八臂聚乙二醇-苯硼酸-甘草酸结合物。该药物递送系统具有多个柔性臂，不仅能够在抗肿瘤方面发挥重要，而且可在病毒表面结合多个S 蛋白，有效地降低病毒对细胞的感染，为抗病毒药物的开发提供新的可能。
发明内容
本发明的目的在于提供一种具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法：首先端基为羧基的八臂聚乙二醇(8arm-PEG-COOH)通过酰胺化反应连接3-氨基苯硼酸(APBA)，而后苯硼酸与甘草酸(GA)的顺式二醇反应形成ROS响应的硼酸酯键，得到8arm-PEG-APBA-GA药物递送系统。
所述的8arm-PEG-APBA-GA结合物的结构如式I所示：
本发明的技术方案如下：
八臂聚乙二醇-苯硼酸-甘草酸结合物的合成：
本发明采用端基为羧基的八臂聚乙二醇作为骨架，3-氨基苯硼酸作为ROS响应单体，甘草酸作为疏水性药物，制备得到了具有ROS智能响应的多作用位点的药物递送系统，其多臂结构不仅可以在抗肿瘤方面提供高的载药量，而且在抗病毒方面可提高甘草酸与S蛋白的结合率，有效抑制病毒感染，为广谱抗病毒药物的开发提供新的方向。
附图说明
图1为八臂聚乙二醇-苯硼酸-甘草酸药物递送系统的合成过程示意图；
图2为八臂聚乙二醇-苯硼酸-甘草酸的红外谱图；
图3为八臂聚乙二醇-苯硼酸-甘草酸的核磁氢谱图；
图4为甘草酸、苯硼酸-甘草酸及八臂聚乙二醇-苯硼酸-甘草酸与SARS-2的S蛋白的分子对接模拟结果。
具体实施方式
下面给出的实例对本发明进行具体描述，但不限制本发明，本发明的范围由权利要求限定。
实施例1：
八臂聚乙二醇-苯硼酸的合成：取八臂聚乙二醇羧基(分子量为10k)0.6g，溶于15mL DMSO，加入0.0920g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.0663gN-羟基琥珀酰亚胺，常温搅拌4h以活化羧基。而后加入0.1315g 3-氨基苯硼酸(APBA)，常温反应48h，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸结合物。
八臂聚乙二醇-苯硼酸-甘草酸的合成：取八臂聚乙二醇-苯硼酸结合物0.3g，溶于10mL DMSO，加入甘草酸0.4938g，分子筛(
)1g，常温搅拌反应8h后，采用透析袋(MWCO3500)透析后，冷冻干燥得到八臂聚乙二醇-苯硼酸-甘草酸结合物。
实施例2：
八臂聚乙二醇-苯硼酸的合成：取八臂聚乙二醇羧基(分子量为20k)0.6g，溶于15mL DMSO，加入0.0552g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.0398gN-羟基琥珀酰亚胺，常温搅拌4h以活化羧基。而后加入0.0986g 3-氨基苯硼酸(APBA)，常温反应48h，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸结合物。
八臂聚乙二醇-苯硼酸-甘草酸的合成：取八臂聚乙二醇-苯硼酸结合物0.4g，溶于10mL DMSO，加入甘草酸0.3950g，分子筛(
)1g，常温搅拌反应8h后，采用透析袋(MWCO3500)透析后，冷冻干燥得到八臂聚乙二醇-苯硼酸-甘草酸结合物。
实施例3：
八臂聚乙二醇-苯硼酸的合成：取八臂聚乙二醇羧基(分子量为40k)0.6g，溶于15mL DMSO，加入0.0184g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.0166gN-羟基琥珀酰亚胺，常温搅拌4h以活化羧基。而后加入0.0394g 3-氨基苯硼酸(APBA)，常温反应48h，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸结合物。
八臂聚乙二醇-苯硼酸-甘草酸的合成：取八臂聚乙二醇-苯硼酸结合物0.4g，溶于10mL DMSO，加入甘草酸0.6583g，分子筛(
)1g，常温搅拌反应8h后，采用透析袋(MWCO3500)透析后，冷冻干燥得到八臂聚乙二醇-苯硼酸-甘草酸结合物。
实施例4：
八臂聚乙二醇-苯硼酸的合成：取八臂聚乙二醇羧基(分子量为40k)0.6g，溶于15mL DMSO，加入0.0192g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.0173gN-羟基琥珀酰亚胺，常温搅拌4h以活化羧基。而后加入0.0548g 3-氨基苯硼酸(APBA)，常温反应48h，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸结合物。
八臂聚乙二醇-苯硼酸-甘草酸的合成：取八臂聚乙二醇-苯硼酸结合物0.4g，溶于10mL DMSO，加入甘草酸0.3292g，分子筛(
)1g，常温搅拌反应8h后，采用透析袋(MWCO3500)纯化48h，冷冻干燥得到八臂聚乙二醇-苯硼酸-甘草酸结合物。
Claims (5)
1.一种具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法，其特征在于，采用端基为羧基的八臂聚乙二醇为柔性多臂骨架，经酰胺化反应连接3-氨基苯硼酸后，通过硼酸酯键与甘草酸化学连接，制备具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统。
2.根据权利要求1所述的具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法，包括如下步骤：
(1)取一定质量的端基为羧基的八臂聚乙二醇溶于DMSO中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)，常温搅拌一段时间以活化羧基，而后加入一定质量的3-氨基苯硼酸，常温搅拌，反应24～72h后，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸结合物；
(2)取一定质量制备得到的八臂聚乙二醇-苯硼酸结合物溶于DMSO，加入一定量的甘草酸和分子筛，常温搅拌反应2～16h后，采用透析袋(MWCO 3500)纯化，冷冻干燥得到八臂聚乙二醇-苯硼酸-甘草酸结合物。
3.根据权利要求1和2所述的一种具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法，其特征在于，步骤(1)中端基为羧基的八臂聚乙二醇的分子量分别为10k，20k和40k，八臂聚乙二醇和EDC的摩尔比为1：4～1：12，EDC和NHS的摩尔比为1：1.2～1：1.5，八臂聚乙二醇和3-氨基苯硼酸的摩尔比为1：20～1：40。
4.根据权利要求1和2所述的一种具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草酸药物递送系统及其制备方法，其特征在于，步骤(2)中八臂聚乙二醇-苯硼酸和甘草酸的摩尔比约为1：16～1：80。
5.根据权利要求1、2、3、4所述的具有ROS智能响应的八臂聚乙二醇-苯硼酸-甘草药物递送系统，可用作广谱抗病毒和抗肿瘤药物。
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