Glucose-responsive complex micelles for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo.
Glucose-responsive complex micelles for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo.
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DOI：
10.1016/j.colsurfb.2019.05.003
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发表时间：
2019-08
期刊：
影响因子：
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通讯作者：
Gang Wu;Chang Li;Xiaoyu Liu;Juan Lv;Yuxun Ding;Yong Liu;Ying Liu;Fan Huang;Linqi Shi
中科院分区：
文献类型：
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作者：
Gang Wu;Chang Li;Xiaoyu Liu;Juan Lv;Yuxun Ding;Yong Liu;Ying Liu;Fan Huang;Linqi Shi
近几十年来，人们开发了大量基于聚氨基酸的葡萄糖反应胶束，用于治疗糖尿病，但由于胶束核可生物降解，缺乏对胰岛素的保护结构，大多数胶束在体内不能有效地保护胰岛素免受酶降解，这在很大程度上降低了胰岛素的疗效。在本研究中，我们制备了一种由苯基硼酸（PBA）修饰的嵌段共聚物PEG-b-P（Asp-co-AspPBA）和葡萄糖胺(GA)/硝基三乙酸（NTA）功能化嵌段共聚物PNIPAM-b-P（Asp-co-AspGA-co-AspNTA）自组装的新型胰岛素负载葡萄糖反应复合物胶束（CMs），用于自我调节胰岛素递送，有效保护胰岛素并增强体内降糖活性。CMs具有PEG/PNIPAM混合壳和PBA/GA交联核，在高葡萄糖浓度（5 g/L）下可分解，在低葡萄糖浓度（1 g/L）下保持稳定。CMs的NTA基团通过特异性结合胰岛素与螯合锌离子，大大提高了胰岛素的负载含量。更重要的是，混合壳中的PNIPAM链在37℃下会坍塌，并在胶束核心周围形成疏水结构域，这可以显著保护胶束核心以及被包裹的胰岛素不受外界蛋白酶的攻击。在1型糖尿病小鼠模型中，NTA螯合胰岛素的CMs具有较长的降糖效果，优于PBS缓冲液（pH 7.4）中不含PNIPAM和胰岛素的负载胰岛素的简单胶束。因此，这种CMs可能是糖尿病治疗中胰岛素输送的潜在候选者。
Large amounts of insulin-loaded glucose-responsive micelles based on poly(amino acid)s have been developed for diabetes treatment over last decades, but most of them could not effectively protect insulin from enzymatic degradationin vivobecause the micellar core was biodegradable and lacked protective structure for insulin, which would lower the efficacy of insulin to a large extent. In this study, we fabricated a new type of insulin-loaded glucose-responsive complex micelles (CMs), which were self-assembled by a phenylboronic acid (PBA)-modified block copolymer PEG-b-P(Asp-co-AspPBA) and a glucosamine (GA)/nitrilotriacetic acid (NTA)-functionalized block copolymer PNIPAM-b-P(Asp-co-AspGA-co-AspNTA), for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activityin vivo. The CMs possessed mixed shell of PEG/PNIPAM and cross-linked core of PBA/GA complex, which could be disintegrated under the condition of high glucose concentration (5 g/L) while maintaining stable at low glucose concentration (1 g/L). The NTA groups of CMs greatly improved the loading content of insulin by specifically bind insulinviathe chelated zinc ions. More importantly, PNIPAM chains in the mixed shell would collapse under 37 °C and form hydrophobic domains around the micellar core, which could significantly protect the micellar core as well as the encapsulated insulin from attacking by external proteases. In a murine model of type 1 diabetes, the CMs with insulin chelated by NTA showed a long hypoglycemic effect, which is superior to insulin-loaded simple micelles without PNIPAM and insulin in PBS buffer (pH 7.4). Therefore, this kind of CMs could be a potential candidate for insulin delivery in diabetes therapy.