Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, CB3 0FF, UK.
Biopharmaceutical Development, MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Nat Commun. 2017 Oct 18;8(1):1026. doi: 10.1038/s41467-017-01114-1.
The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.
使用肽作为治疗剂正在复兴，人们期望新的药物具有更高的疗效和安全性。一旦精确控制了它们的物理化学和药代动力学特性，它们的临床潜力才会得到充分实现。在这里，我们展示了一种可逆的肽自组装策略，以控制和延长体内天然肽激素的生物活性。我们表明，具有治疗肥胖症和糖尿病潜力的胃泌素释放肽会自组装成稳定的纳米纤维制剂，随后纳米纤维制剂解离以释放活性肽，并在体内产生药理作用。在大鼠中皮下给予纳米纤维可大大延长其暴露时间，与游离胃泌素释放肽相比，血清中至少可检测到 5 天的恒定胃泌素释放肽生物活性，而游离胃泌素释放肽仅在 4 小时后就无法检测到。这种方法简单、具有成本效益且通用，可以解决肽治疗的局限性。
