基于温度和葡萄糖双重响应性共聚物微囊的胰岛素控释载体

doi:10.16085/j.issn.1000-6613.2023-0853

摘要/Abstract

摘要：

糖尿病治疗的进展期于找到能够实时监测机体血糖水平并精确释放所需剂量胰岛素的载体材料，因此开发可根据葡萄糖浓度变化情况而进行自我调节的智能胰岛素控释载体具有重要的临床应用价值。鉴于此，本文创建了一种可用于胰岛素控制释放的温度和葡萄糖双重响应性共聚物微囊的制备策略。首先采用自由基聚合法合成以N-异丙基丙烯酰胺（NIPAAm）和3-丙烯酰胺基苯硼酸（AAPBA）为主要成分的无规共聚物，运用底喷包衣技术在玻璃微球表面包覆共聚物涂层，然后通过加热退火使共聚物固定接枝于微球表面，利用氢氟酸溶解模板，从而形成共聚物微囊，同时对其化学组成、尺寸分布、平衡溶胀率、表面形貌、稳定性能、细胞毒性及胰岛素控释能力进行测试分析。结果表明，该共聚物微囊尺寸分布相对均匀，稳定性良好，无细胞毒性，具有显著的温敏性和糖敏性，且可利用其双重响应特性进行胰岛素瘤细胞的固定负载和分泌胰岛素的控制释放。此智能响应性胰岛素控释载体的制备方案可为人工胰腺的构建提供崭新思路及技术支持。

关键词: 复合材料, 聚合物, 凝胶, 载体, 多孔介质, 温度敏感性, 葡萄糖敏感性

Abstract:

The treatment of diabetes is to seek the carriers that can monitor the blood glucose level immediately and release the required dosage of insulin accurately. Therefore, the development of intelligent insulin controlled release carriers that can self-regulate according to the change of glucose concentration has important clinical application values. This work creates a feasible strategy for the preparation of temperature and glucose dual-response copolymer microcapsules that can be used for insulin controlled release. Firstly, random copolymers with N-isopropylacrylamide (NIPAAm) and 3-acrylamidophenylboronic acid (AAPBA) as the main components were synthesized by free radical polymerization. The surfaces of glass microspheres were covered with copolymer solution by bottom-spray coating technology. Then the copolymers were grafted on the surfaces of the microspheres by heating and annealing, and the templates were dissolved by hydrofluoric acid to form the copolymer microcapsules. The chemical composition, size distribution, equilibrium swelling, surface morphology, stability, cytotoxicity and controlled release capacity of insulin were investigated and analyzed. The results showed that the copolymer microcapsules had relatively uniform size distribution, good stability, no cytotoxicity, significant temperature and glucose sensitivity, and could be applied for loading of insulinoma cells, as well as controlled release of secreted insulin. The scheme for preparing the smart responsive insulin controlled release carriers has access to a powerful tool for creating artificial pancreas.

Key words: composites, polymers, gels, support, porous media, temperature sensitivity, glucose sensitivity

中图分类号:

O633

杨磊, 邱广薇, 李思言, 葛宏程, 孙园园, 王菲, 范晓光. 基于温度和葡萄糖双重响应性共聚物微囊的胰岛素控释载体[J]. 化工进展, 2024, 43(6): 3277-3284.

YANG Lei, QIU Guangwei, LI Siyan, GE Hongcheng, SUN Yuanyuan, WANG Fei, FAN Xiaoguang. Insulin controlled release carriers based on temperature and glucose dual-response copolymer microcapsules[J]. Chemical Industry and Engineering Progress, 2024, 43(6): 3277-3284.

图/表 7

图1 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物微囊的制备策略

图2 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物及其微囊的ATR-FTIR谱图

图3 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物微囊的尺寸分布和平衡溶胀[**表示显著性差异(p<0.01)]

图4 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物微囊的表面形貌

表1 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物微囊的稳定性

浸泡条件	剩余质量分数/%
浸泡条件	0d	7d	14d	21d	28d
去离子水20℃	100	99.38±0.21	98.32±0.25	96.67±0.26	95.57±0.35
去离子水37℃	100	99.41±0.18	98.16±0.21	96.19±0.15	95.29±0.42
PBS溶液20℃	100	99.45±0.20	98.50±0.29	97.04±0.17	96.05±0.27
PBS溶液37℃	100	99.46±0.09	98.52±0.25	96.90±0.30	95.93±0.32
葡萄糖溶液20℃	100	99.52±0.18	98.39±0.29	96.34±0.26	95.55±0.38
葡萄糖溶液37℃	100	99.25±0.22	98.06±0.28	96.54±0.39	95.42±0.23

图5 P(NIPAAm-co-AAPBA-co-HPM-co-TMSPM)共聚物微囊的细胞毒性

图6 微囊化βTC6细胞的胰岛素控制释放

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