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治疗性蛋白质共价结合蛋白质抗性聚合物是被广泛使用的延长其体内半衰期的方法.然而,聚合物的分子量对蛋白质-聚合物偶联物体外和体内性能的影响尚未得到很好的阐明.本文报道了聚(寡聚乙二醇甲基丙烯酸酯)(POEGMA)的分子量对C末端修饰干扰素-α(IFN)-POEGMA偶联物的体外和体内性能的影响.增加POEGMA的分子量会降低IFN-α的体外活性,但改善了其热稳定性和体内药代动力学.IFN-α的体内抗肿瘤功效随着POEGMA分子量从20增加至60 kDa而增强,但进一步提高POEGMA的分子量到100 kDa,由于其生物活性的降低中和了药代动力学的改善作用,并不能进一步增强其体内抗肿瘤功效.该发现为蛋白质-聚合物偶联物分子尺寸效应提供了新的佐证,可为设计下一代蛋白质-聚合物偶联物提供参考,通过减少给药频率和不良反应并改善治疗效果而使患者受益.
Therapeutic proteins Covalently-bound protein-resistant polymers are widely used to prolong their half-life in vivo, however, the effect of polymer molecular weight on the in vitro and in vivo performance of protein-polymer conjugates has not been well elucidated. The effect of the molecular weight of poly (ethylene glycol monomethacrylate) (POEGMA) on the in vitro and in vivo performance of C-terminal modified interferon-alpha (IFN) -POEGMA conjugates is reported in this paper. Increasing the molecular weight of POEGMA decreases IFN-alpha in vitro but improved its thermal stability and in vivo pharmacokinetics.The in vivo antitumor efficacy of IFN- [alpha] increases as the molecular weight of POEGMA increases from 20 to 60 kDa, but further increases the molecular weight of POEGMA to 100 kDa, due to its reduced bioactivity and neutralization of the pharmacokinetic ameliorating effects, does not further enhance its antitumor efficacy in vivo.The finding provides new evidence for the molecular size effect of protein-polymer conjugates, which may be Designing the next generation of protein-polymer conjugates provides a reference that benefits patients by reducing dosing and adverse reactions and improving treatment outcomes.