Improved antitumor activity and tumor targeting of NH2-terminal- specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand

Su Young Chae, Tae Hyung Kim, Kyeongsoon Park, Cheng Hao Jin, Sohee Son, Seulki Lee, Yu Seok Youn, Kwang Meyung Kim, Dong Gyu Jo, Ick Chan Kwon, Xiaoyuan Chen, Kang Choon Lee

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1719-1729
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number6
DOIs
Publication statusPublished - 2010 Jun 1
Externally publishedYes

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Pharmacokinetics
Neoplasms
Solubility
Biological Therapy
Heterografts
Antineoplastic Agents
PEGylated tumor necrosis factor-related apoptosis-inducing ligand
Therapeutics
Animal Models
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Improved antitumor activity and tumor targeting of NH2-terminal- specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand. / Chae, Su Young; Kim, Tae Hyung; Park, Kyeongsoon; Jin, Cheng Hao; Son, Sohee; Lee, Seulki; Youn, Yu Seok; Kim, Kwang Meyung; Jo, Dong Gyu; Kwon, Ick Chan; Chen, Xiaoyuan; Lee, Kang Choon.

In: Molecular Cancer Therapeutics, Vol. 9, No. 6, 01.06.2010, p. 1719-1729.

Research output: Contribution to journalArticle

Chae, Su Young ; Kim, Tae Hyung ; Park, Kyeongsoon ; Jin, Cheng Hao ; Son, Sohee ; Lee, Seulki ; Youn, Yu Seok ; Kim, Kwang Meyung ; Jo, Dong Gyu ; Kwon, Ick Chan ; Chen, Xiaoyuan ; Lee, Kang Choon. / Improved antitumor activity and tumor targeting of NH2-terminal- specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 6. pp. 1719-1729.
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