Pan Li-Qiang, Zhao Wen-Bin, Lai Jun, Ding Ding, Wei Xiao-Yue, Li Yang-Yang, Liu Wen-Hui, Yang Xiao-Yue, Xu Ying-Chun, Chen Shu-Qing
Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Zhejiang Hisun Pharmaceutical Inc, 46 Waisha Road, Jiaojiang District, 317000 Taizhou, China.
Sci Rep. 2015 Oct 8;5:14872. doi: 10.1038/srep14872.
Poor pharmacokinetics and resistance within some tumor cell lines have been the major obstacles during the preclinical or clinical application of TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand). The half-life of TRAIL114-281 (114 to 281 amino acids) was revealed to be no more than 30 minutes across species. Therefore maleimido activated PEG (polyethylene glycol) and MMAE (Monomethyl Auristatin E) were applied to site-specifically conjugate with the mutated cysteines from different monomers of TRAIL successively, taking advantage of steric effects involved within TRAIL mutant conjugations. As a result, TRAIL trimer was hetero-modified for different purposes. And the resulting PEG-TRAIL-vcMMAE conjugate exhibited dramatically improved half-life (11.54 h), favourable in vivo targeting capability and antitumor activities while no sign of toxicity in xenograft models, suggesting it's a viable therapeutic and drug delivery strategy.
在TRAIL（肿瘤坏死因子（TNF）相关凋亡诱导配体）的临床前或临床应用过程中，某些肿瘤细胞系中较差的药代动力学和耐药性一直是主要障碍。已发现TRAIL114 - 281（114至281个氨基酸）在不同物种中的半衰期不超过30分钟。因此，利用TRAIL突变体缀合物中涉及的空间效应，将马来酰亚胺活化的聚乙二醇（PEG）和单甲基奥瑞他汀E（MMAE）先后用于与TRAIL不同单体中的突变半胱氨酸进行位点特异性缀合。结果，TRAIL三聚体因不同目的而进行了异源修饰。所得的PEG - TRAIL - vcMMAE缀合物表现出显著改善的半衰期（11.54小时）、良好的体内靶向能力和抗肿瘤活性，而异种移植模型中没有毒性迹象，表明这是一种可行的治疗和药物递送策略。
