title: PEGylated TNF-related apoptosis-inducing ligand (TRAIL) analogues: pharmacokinetics and antitumor effects.
abstract: The low stability and fast clearance of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) are the main obstacles to its implementation as an antitumor agent. Here, we attempted to improve its pharmacokinetic and pharmacodynamic profiles by using PEGylation. N-terminal PEGylated TRAIL (PEG-TRAIL) was synthesized using 2, 5, 10, 20, and 30 kDa PEG. Antitumor effect assessments in HCT116 tumor bearing nude mice showed that all PEG-TRAIL analogues efficiently suppressed mean tumor growth, with mean tumor growth inhibition (TGI) values (5K-, 20K-, 30K-PEG-TRAIL) of 43.5, 61.7, and 72.3%, respectively. In particular, 30K-PEG-TRAIL was found to have antitumor efficacy for five days after a single administration (1 mg/mouse, i.p.). The different antitumor effects of these PEG-TRAIL analogues were attributed to augmented pharmacokinetics and metabolic resistance. All analogues were found to have higher metabolic stabilities in rat plasma, extended pharmacokinetic profiles, and greater circulating half-lives (3.9, 5.3, 6.2, 12.3, and 17.7 h for 2, 5, 10, 20, and 30K-PEG-TRAIL, respectively, versus 1.1 h for TRAIL, i.p.) in ICR mice. Our findings suggest that TRAIL derivatized with PEG of an appropriate M(w) might be useful antitumor agent with protracted activity.
authors.affiliation: College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-ku, Suwon City 440-746, Korea.
authors.forename: Tae Hyung
authors.initials: TH
authors.lastname: Kim
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.forename: Hai Hua
authors.initials: HH
authors.lastname: Jiang
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C552093:PEGylated tumor necrosis factor-related apoptosis-inducing ligand; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D011092:Polyethylene Glycols