Chen Weike, Yu Sihan, Webber Bernice, DeWolf Emily L, Kilmer Rory, Xian Sijie, Schmidt Connor R, Power Elizabeth M, Webber Matthew J
Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA.
J Biomed Mater Res A. 2025 Jan;113(1):e37854. doi: 10.1002/jbm.a.37854.
Precise blood glucose control continues to be a critical challenge in the treatment and management of type 1 diabetes in order to mitigate both acute and chronic complications. This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates the efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders.
在1型糖尿病的治疗和管理中，精确控制血糖仍然是一项关键挑战，以减轻急性和慢性并发症。本研究调查了一种用苯硼酸（PBA）功能化的超分子肽两亲物（PA）材料用于葡萄糖响应性胰高血糖素递送的开发情况。在生理葡萄糖水平存在的情况下，PA-PBA系统自组装成纳米纤维水凝胶，形成能够在低血糖条件下释放胰高血糖素的稳定水凝胶。葡萄糖响应性由PBA与葡萄糖之间的可逆结合驱动，这调节了水凝胶形成和溶解所需的静电相互作用。通过包括圆二色性、zeta电位测量和流变学评估在内的全面体外表征，发现PA-PBA系统表现出葡萄糖依赖性组装，实现了与葡萄糖浓度成反比的可控胰高血糖素释放。在低葡萄糖条件下（模拟低血糖状态），胰高血糖素释放加速，而在较高葡萄糖水平下释放速率降低。使用1型糖尿病小鼠模型在体内对该平台进行评估，证明了其在胰岛素过量后通过恢复血糖水平来预防胰岛素诱导的低血糖的功效。根据波动的葡萄糖浓度调整胰高血糖素释放的能力突出了该平台改善血糖控制的潜力。这些发现表明，葡萄糖稳定的超分子肽水凝胶在响应性药物递送应用中具有巨大潜力，为管理糖尿病和其他代谢紊乱中的血糖水平提供了一种方法。
