PEGylated TNF-Related Apoptosis-Inducing Ligand (TRAIL) Analogues: Pharmacokinetics and Antitumor Effects
| Autor: | Hai Hua Jiang, Tae Hyung Kim, Kang Choon Lee, Seulki Lee, Xiaoyuan Chen, Yu Seok Youn |
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| Rok vydání: | 2011 |
| Předmět: |
Recombinant Fusion Proteins
Biomedical Engineering Mice Nude Pharmaceutical Science Antineoplastic Agents Bioengineering Pharmacology Polyethylene Glycols TNF-Related Apoptosis-Inducing Ligand Mice Structure-Activity Relationship TNF-Related Apoptosis Inducing Ligand TRAIL Drug Stability Pharmacokinetics Cell Line Tumor PEG ratio Animals Humans Structure–activity relationship Chemistry Organic Chemistry Neoplasms Experimental Ligand (biochemistry) Rats Tumor Burden Pharmacodynamics PEGylation Tumor necrosis factor alpha Biotechnology |
| Zdroj: | Bioconjugate Chemistry. 22:1631-1637 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/bc200187k |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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