Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, PR China; Biomedical Engineering Department, Peking University, Beijing 100191, PR China; CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PR China.
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, PR China.
J Control Release. 2020 Dec 10;328:444-453. doi: 10.1016/j.jconrel.2020.08.065. Epub 2020 Sep 6.
Polypeptides are useful in designing protein-polypeptide conjugates for therapeutic applications; however, they are not satisfactory in improving the stability of therapeutic proteins and extending their in vivo half-life. Here we show that thermally-induced self-assembly (TISA) of elastin-like polypeptide diblock copolymer fused interferon alpha (IFNα-ELP) into a spherical micelle can dramatically enhance the proteolytic stability of IFNα. Notably, the circulation half-life of IFNα-ELP micelle (54.7 h) is 124.3-, 5.7-, and 1.4-time longer than those of free IFNα (0.44 h), freely soluble IFNα-ELP (9.6 h), and PEGylated IFNα (39.0 h), respectively. Importantly, in a mouse model of ovarian tumor, IFNα-ELP micelle exhibited significantly enhanced tumor retention and antitumor efficacy over free IFNα, freely soluble IFNα-ELP, and even PEGylated IFNα. These findings provide a thermoresponsive supramolecular strategy of TISA to design protein-diblock copolypeptide conjugate micelles with enhanced stability and pharmacology.
多肽在设计用于治疗应用的蛋白质-多肽缀合物方面很有用；然而，它们在提高治疗性蛋白质的稳定性和延长其体内半衰期方面并不令人满意。在这里，我们表明，热诱导自组装（TISA）弹性蛋白样多肽二嵌段共聚物融合干扰素α（IFNα-ELP）成球形胶束可以显著提高 IFNα 的蛋白水解稳定性。值得注意的是，IFNα-ELP 胶束的循环半衰期（54.7 h）分别比游离 IFNα（0.44 h）、自由可溶的 IFNα-ELP（9.6 h）和聚乙二醇化 IFNα（39.0 h）长 124.3、5.7 和 1.4 倍。重要的是，在卵巢肿瘤的小鼠模型中，IFNα-ELP 胶束在肿瘤保留和抗肿瘤功效方面明显优于游离 IFNα、自由可溶的 IFNα-ELP，甚至优于聚乙二醇化 IFNα。这些发现提供了一种热响应性超分子策略，用于设计具有增强稳定性和药理学特性的蛋白质-二嵌段共聚酯胶束。
