Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, United Kingdom.
Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
Front Endocrinol (Lausanne). 2023 Jul 24;14:1217021. doi: 10.3389/fendo.2023.1217021. eCollection 2023.
Oxyntomodulin (Oxm) hormone peptide has a number of beneficial effects on nutrition and metabolism including increased energy expenditure and reduced body weight gain. Despite its many advantages as a potential therapeutic agent, Oxm is subjected to rapid renal clearance and protease degradation limiting its clinical application. Previously, we have shown that subcutaneous administration of a fibrillar Oxm formulation can significantly prolong its bioactivity from a few hours to a few days.
We used a protease resistant analogue of Oxm, Aib2-Oxm, to form nanfibrils depot and improve serum stability of released peptide. The nanofibrils and monomeric peptide in solution were characterized by spectroscopic, microscopic techniques, potency assay, QCM-D and studies.
We show that in comparison to Oxm, Aib2-Oxm fibrils display a slower elongation rate requiring higher ionic strength solutions, and a higher propensity to dissociate. Upon subcutaneous administration of fibrillar Aib2-Oxm in rodents, a 5-fold increase in bioactivity relative to fibrillar Oxm and a significantly longer bioactivity than free Aib2-Oxm were characterized. Importantly, a decrease in food intake was observed up to 72-hour post-administration, which was not seen for free Aib2-Oxm.
Our findings provides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced pharmacological response.
氧结合蛋白（Oxm）激素肽对营养和代谢有许多有益的影响，包括增加能量消耗和减少体重增加。尽管作为一种潜在的治疗剂具有许多优点，但 Oxm 易被肾脏快速清除和蛋白酶降解，限制了其临床应用。以前，我们已经表明，皮下给予纤维状 Oxm 制剂可以将其生物活性从几个小时延长到几天。
我们使用 Oxm 的蛋白酶抗性类似物 Aib2-Oxm 来形成纳米纤维库并提高释放肽的血清稳定性。通过光谱学、显微镜技术、效力测定、QCM-D 和 研究对纳米纤维和溶液中的单体肽进行了表征。
与 Oxm 相比，我们表明 Aib2-Oxm 纤维显示出较慢的延伸速率，需要更高的离子强度溶液，并且更容易解离。在啮齿动物中皮下给予纤维状 Aib2-Oxm 后，与纤维状 Oxm 相比，生物活性增加了 5 倍，并且比游离 Aib2-Oxm 的生物活性明显延长。重要的是，在给药后 72 小时观察到摄食量下降，而游离 Aib2-Oxm 则没有观察到。
我们的发现为开发长效肽纤维制剂提供了有力的证据，这些制剂可延长血浆暴露和增强 药理反应。
