Improved Antitumor Activity and Tumor Targeting of NH2-Terminal-Specific PEGylated Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
- Improved Antitumor Activity and Tumor Targeting of NH2-Terminal-Specific PEGylated Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand
- 채수영; 김태현; 박경순; Cheng-Hao Jin; 손소희; 이슬기; 윤유석; 김광명; 조동규; 권익찬; Xiaoyuan Chen; 이강춘
- Issue Date
- Molecular cancer therapeutics
- VOL 9, NO 6, 1719-1729
- Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell–specific cytotoxicity. However, its low stability, solubility, unexpected side effects, and weak pharmacokinetic profiles restrict its successful clinical application. To develop efficient TRAIL-based anticancer biotherapeutics, a new version of trimeric TRAIL was constructed by incorporating trimer-forming zipper sequences (HZ-TRAIL), and then NH2-terminal–specific PEGylation was done to produce PEGylated TRAIL (PEG-HZ-TRAIL). The biological, physicochemical, and pharmaceutical characteristics of PEG-HZ-TRAIL were then investigated using various in vitro and in vivo experiments, including a cell-based cytotoxicity test, a solubility test, pharmacokinetic analysis, and antitumor efficacy evaluations. Although slight activity loss occurred after PEGylation, PEG-HZ-TRAIL showed excellent tumor cell–specific cytotoxic effects via apoptotic pathways with negligible normal cell toxicity. The stability and pharmacokinetic problems of HZ-TRAIL were successfully overcome by PEGylation. Furthermore, in vivo antitumor tests revealed that PEG-HZ-TRAIL treatment enhanced therapeutic potentials compared with HZ-TRAIL in tumor xenograft animal models, and these enhancements were attributed to its better pharmacokinetic properties and tumor-targeting performance. These findings show that PEG-HZ-TRAIL administration provides an effective antitumor treatment, which exhibits superior tumor targeting and better inhibits tumor growth, and suggest that PEG-HZ-TRAIL should be considered a potential candidate for antitumor biotherapy.
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