CN110358096A - 亚麻酸修饰的单甲氧基聚乙二醇-聚乙烯亚胺及其制备 - Google Patents

亚麻酸修饰的单甲氧基聚乙二醇-聚乙烯亚胺及其制备 Download PDF

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CN110358096A
CN110358096A CN201910455286.5A CN201910455286A CN110358096A CN 110358096 A CN110358096 A CN 110358096A CN 201910455286 A CN201910455286 A CN 201910455286A CN 110358096 A CN110358096 A CN 110358096A
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冯润良
宋智梅
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Abstract

本发明主要涉及亚麻酸修饰单甲氧基聚乙二醇‑聚乙烯亚胺聚合物及其制备。单甲氧基聚乙二醇‑聚乙烯亚胺为起始原料，经选择性N‑酰化反应，在聚乙烯亚胺链段引入alfa‑或gamma‑亚麻酸，制备得到亚麻酸修饰单甲氧基聚乙二醇‑聚乙烯亚胺聚合物。

Description

亚麻酸修饰的单甲氧基聚乙二醇-聚乙烯亚胺及其制备
技术领域
本发明主要涉及亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物及其制备，属于化学合成技术领域。
背景技术
单甲氧基聚乙二醇-聚乙烯亚胺是一种水溶性多氨基聚电聚合物。一方面，可经静电作用包载负电性药物，用于疾病的防治。另一方面，可经氨基修饰引入亲脂性分子，形成两亲性聚合物，降低自身的毒性，并用于亲脂性药物的包载，实现药物的靶向递送、缓释以及药代动力学性质改善等目标。
alfa-亚麻酸是一种天然亲脂性多不饱和脂肪酸，具有抗菌、抗氧化、抗炎、抗癌、心脏保护以及神经保护等多种药理活性（Food and Chemical Toxicology, 2014, 70,163-178）。类似地，gamma-亚麻酸具有抗炎（Current Pharmaceutical Biotechnology,2006, 7(6), 531-534）、协同抗癌（International Journal of Cancer, 2000, 85(5),643-648）。因此，将亚麻酸引入单甲氧基聚乙二醇-聚乙烯亚胺中，将得到两亲性聚合物。该聚合物自组装所形成的胶束、纳米粒等可用于抗癌、抗菌、抗炎等药物的包载，以改善药物的释放特性、活性、稳定性或药代动力学性质等。
发明内容
本发明提供了一种亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物，其亲水性链段为单甲氧基聚乙二醇-聚乙烯亚胺，疏水性链段为alfa-或gamma-亚麻酸，结构式如下：
和
式中，t=14或52；
y=1-30；
单甲氧基聚乙二醇的分子量为2000、4000、5000、10000或20000，对应的n=44、90、113、226、454。
该亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物的制备方法，其特征是包括以下反应步骤：
具体反应主要是：
alfa-或gamma-亚麻酸经经等摩尔比的N-羟基丁二酰亚胺与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐活化后，加入参照文献（Biological & Pharmaceutical Bulletin,2003, 26(4):492-500）制备的单甲氧基聚乙二醇-聚乙烯亚胺，进行选择性N-酰化反应，得到亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物。
上述步骤中，N-羟基丁二酰亚胺与alfa-或gamma-亚麻酸的摩尔比均为1:1-1:2；1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与alfa-或gamma-亚麻酸的摩尔比均为1:1-1:2；N-羟基丁二酰亚胺与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为1:1。
上述步骤中，反应介质为二氯甲烷、氯仿、二甲基亚砜或N, N-二甲基甲酰胺中的一种。
上述步骤中，反应温度为15-35℃，反应时间为6-24 h。
本发明提供了一种亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺聚合物以及以单甲氧基聚乙二醇-聚乙烯亚胺为起始原料制备亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺聚合物的制备方法。即在N-羟基丁二酰亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐等存在条件下，单甲氧基聚乙二醇-聚乙烯亚胺经alfa-或gamma-亚麻酸N-酰化反应，得到亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺聚合物。
本发明所得亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺聚合物是在聚乙烯亚胺一端引入alfa-或gamma-亚麻酸，以便于形成两亲性聚电聚合物，用于亲脂性药物包载，实现药物活性、稳定性、缓释性或药代动力学性质等的改善。
具体实施方式
单甲氧基聚乙二醇、聚乙烯亚胺的名称说明如下：
分子量为2000的单甲氧基聚乙二醇记为单甲氧基聚乙二醇2000，分子量为600的聚乙烯亚胺记为聚乙烯亚胺600。其余，以此类推。
下面结合实施例对本发明作进一步的说明，下述说明仅是为了解释本发明，并不对其内容进行限定。
亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺聚合物的合成
方法一：在干燥反应瓶中， N-羟基丁二酰亚胺（414 mg, 3.6 mmol）、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（689 mg, 3.6 mmol）、alfa-亚麻酸（830 mg, 3 mmol）与无水二氯甲烷混合溶解后，室温反应4 h。将单甲氧基聚乙二醇2000-聚乙烯亚胺600（4 g, 1.5mmol）加入其中，同温继续反应24 h。减压蒸馏除去大部分溶剂，加入50 mL无水乙醚沉淀，抽滤。将所得白色固体溶于尽量少的二氯甲烷中，用10倍量无水乙醚沉淀。重复上述过程一次，得白色固体3.82 g，收率为80%；
方法二：在干燥反应瓶中，N-羟基丁二酰亚胺（828 mg, 7.2 mmol）、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（1.378 g, 7.2 mmol）、gamma-亚麻酸（1.66. g, 6 mmol）与N,N-二甲基甲酰胺混合溶解后，室温反应4 h。将单甲氧基聚乙二醇5000-聚乙烯亚胺600（8.48 g, 1.5 mmol）加入其中，同温继续反应24 h。透析，冻干，得白色固体8.13 g，收率为81%；
方法三：在干燥反应瓶中， N-羟基丁二酰亚胺（1.38 g, 12 mmol）、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（2.3 g, 12 mmol）、gamma-亚麻酸（2.78 g, 10 mmol）与无水氯仿混合溶解后，室温反应4 h。将单甲氧基聚乙二醇10000-聚乙烯亚胺1800（11.86 g, 1mmol）加入其中，同温继续反应24 h。减压蒸馏除去大部分溶剂，加入50 mL无水乙醚沉淀，抽滤。将所得白色固体溶于尽量少的氯仿中，用10倍量无水乙醚沉淀。重复上述过程一次，得白色固体12.3 g，收率为85%；
方法四：在干燥反应瓶中，N-羟基丁二酰亚胺（1.38 g, 12 mmol）、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（2.3 g, 12 mmol）、alfa-亚麻酸（2.78 g, 10 mmol）与二甲基亚砜混合溶解后，室温反应4 h。将单甲氧基聚乙二醇20000-聚乙烯亚胺1800（10.9 g, 0.5mmol）加入其中，同温继续反应24 h。透析，冻干，得白色固体10.8 g，收率为80%。

Claims (5)

1.亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物，其亲水性链段为单甲氧基聚乙二醇-聚乙烯亚胺，疏水性链段为alfa-或gamma-亚麻酸，结构式如下：
和
式中，t=14或52；
y=1-30；
单甲氧基聚乙二醇的分子量为2000、4000、5000、10000或20000，对应的n=44、90、113、226、454。
2.该亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物的制备方法，其特征是包括以下反应步骤：
alfa-或gamma-亚麻酸经等摩尔比的N-羟基丁二酰亚胺与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐活化后，将单甲氧基聚乙二醇-聚乙烯亚胺加入，进行选择性N-酰化反应，得到亚麻酸修饰单甲氧基聚乙二醇-聚乙烯亚胺两亲性聚合物。
3.根据权利要求2所述的制备方法，其特征是：N-羟基丁二酰亚胺与alfa-或gamma-亚麻酸的摩尔比均为1:1-1:2；1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与alfa-或gamma-亚麻酸的摩尔比均为1:1-1:2，N-羟基丁二酰亚胺与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为1:1。
4.根据权利要求2所述的制备方法，其特征是：反应介质为二氯甲烷、氯仿、二甲基亚砜或N, N-二甲基甲酰胺中的一种。
5.根据权利要求2所述的制备方法，其特征是：反应温度为15-35℃，反应时间为6-24h。
CN201910455286.5A 2019-05-29 2019-05-29 亚麻酸修饰的单甲氧基聚乙二醇-聚乙烯亚胺及其制备 Pending CN110358096A (zh)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN103275329A (zh) * 2013-06-18 2013-09-04 上海交通大学医学院附属新华医院 一种聚乙二醇修饰的聚乙烯亚胺衍生物及其制备方法
CN104910387A (zh) * 2014-12-25 2015-09-16 上海交通大学 聚乙二醇(peg)化小分子量pei衍生物、制备方法、用途及其复合物

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Publication number Priority date Publication date Assignee Title
CN103275329A (zh) * 2013-06-18 2013-09-04 上海交通大学医学院附属新华医院 一种聚乙二醇修饰的聚乙烯亚胺衍生物及其制备方法
CN104910387A (zh) * 2014-12-25 2015-09-16 上海交通大学 聚乙二醇(peg)化小分子量pei衍生物、制备方法、用途及其复合物

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