Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
Biomater Sci. 2024 Nov 5;12(22):5742-5752. doi: 10.1039/d4bm01163e.
PEGylation is a promising strategy for modulating the physicochemical properties and improving the therapeutic efficacy of protein drugs. However, the application of multi-PEGylation frequently results in diminished protein activity. A single low molecular weight PEG (5 kDa) modified at the amino terminus of the B chain preserves the biological activity of insulin and moderately improves its pharmacokinetics. Nonetheless, this modification offers limited protein stabilization. Furthermore, overdoses still carry the risk of hypoglycemia, posing challenges for the clinical application of PEGylated insulin. Here, we constructed multifunctional nanochaperones featuring phenylboronic acid (PBA) modified hydrophobic microdomains and nitrilotriacetic acid (NTA)-based coordination domains (PN-nChaps) for PEGylated insulin delivery. This delivery strategy effectively overcomes the limitations associated with PEGylation by enhancing the stability and reducing the immunogenicity of PEGylated insulin, while enabling glucose-responsive controlled release. PEGylated insulin with nanochaperone carrier demonstrates a prolonged half-life ( = 18.66 h), facilitates on-demand release, and minimizes the risk of hypoglycemia. This approach provides a safe and effective strategy for long-term glycemic management in diabetic patients.
聚乙二醇化是一种有前途的策略，可以调节蛋白质药物的物理化学性质并提高其治疗效果。然而，多聚乙二醇化的应用常常导致蛋白质活性降低。单低分子量聚乙二醇（5 kDa）修饰在 B 链的氨基末端可保持胰岛素的生物活性并适度改善其药代动力学。然而，这种修饰提供的蛋白质稳定性有限。此外，过量用药仍有发生低血糖的风险，这给聚乙二醇化胰岛素的临床应用带来了挑战。在这里，我们构建了具有芐基硼酸（PBA）修饰的疏水性微区和基于氮三乙酸（NTA）的配位域的多功能纳米分子伴侣（PN-nChaps），用于聚乙二醇化胰岛素的递送。这种递送策略通过增强聚乙二醇化胰岛素的稳定性和降低其免疫原性，同时实现葡萄糖响应性控制释放，有效地克服了聚乙二醇化的局限性。带有纳米分子伴侣载体的聚乙二醇化胰岛素具有延长的半衰期（t1/2 = 18.66 h），可实现按需释放，并最大限度地降低低血糖风险。这种方法为糖尿病患者的长期血糖管理提供了一种安全有效的策略。
