Department of Chemistry and Chemical Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China.
Sci China Life Sci. 2013 Jan;56(1):51-8. doi: 10.1007/s11427-012-4431-7. Epub 2013 Jan 12.
To design a releasable PEGylated TNF-α (rPEG-TNF-α), a cathepsin B-sensitive dipeptide (Val-Cit moiety) was inserted into conventional PEG-modified TNF-α (PEG-TNF-α), facilitating its clinical use for anti-tumor therapy. Comparative pharmacokinetic and pharmacodynamic studies showed that the half-lives of both PEGylated forms of TNF-α were ∼60-fold greater than that of unmodified TNF-α. In addition, the in vitro bioactivity of rPEG-TNF-α was greater than that of PEG-TNF-α with the same degree of PEG modification. Release of TNF-α from rPEG-TNF-α in vitro was dependent on the presence of cathepsin B and was inhibited by a cathepsin B inhibitor. Despite the potent cytotoxicity of unmodified TNF-α against normal cells, its PEGylated forms at higher TNF-α concentrations showed low cytotoxic activity against these cells. In contrast, both forms of PEGylated TNF-α showed potent cytotoxic activity against the B16 and L929 cell lines, with rPEG-TNF-α being 5- and 9-fold more potent, respectively, than PEG-TNF-α. Moreover, rPEG-TNF-α was a more potent in vivo antitumor agent than PEG-TNF-α.
为了设计一种可释放的聚乙二醇化肿瘤坏死因子-α（rPEG-TNF-α），将一种组织蛋白酶 B 敏感二肽（缬氨酰-瓜氨酸部分）插入常规的聚乙二醇化修饰的肿瘤坏死因子-α（PEG-TNF-α）中，使其更有利于临床用于抗肿瘤治疗。比较药代动力学和药效学研究表明，两种聚乙二醇化形式的 TNF-α 的半衰期均比未修饰的 TNF-α 长约 60 倍。此外，rPEG-TNF-α 的体外生物活性大于具有相同聚乙二醇修饰程度的 PEG-TNF-α。rPEG-TNF-α 体外从 rPEG-TNF-α 中的释放依赖于组织蛋白酶 B 的存在，并被组织蛋白酶 B 抑制剂抑制。尽管未修饰的 TNF-α 对正常细胞具有强烈的细胞毒性，但在较高 TNF-α 浓度下，其聚乙二醇化形式对这些细胞的细胞毒性活性较低。相比之下，两种形式的 PEG-TNF-α 对 B16 和 L929 细胞系均具有强烈的细胞毒性活性，rPEG-TNF-α 的活性分别比 PEG-TNF-α 高 5 倍和 9 倍。此外，rPEG-TNF-α 是一种比 PEG-TNF-α 更有效的体内抗肿瘤药物。
