title: Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities.
abstract: 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.
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Pan
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Zhao
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lai
authors.affiliation: Zhejiang Hisun Pharmaceutical Inc, 46 Waisha Road, Jiaojiang District, 317000 Taizhou, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ding
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Xiao-Yue
authors.initials: XY
authors.lastname: Wei
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Li
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Xiao-Yue
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Xu
authors.affiliation: Institute of Drug metabolism and Drug analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D020014:K562 Cells; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D053221:TNF-Related Apoptosis-Inducing Ligand; D011092:Polyethylene Glycols; C495575:monomethyl auristatin E