Improved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.
Improved antitumor activity and tumor targeting of NH(2)-terminal-specific PEGylated tumor necrosis factor-related apoptosis-inducing ligand.
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DOI：
10.1158/1535-7163.mct-09-1076
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发表时间：
2010-06
影响因子：
5.7
通讯作者：
Lee KC
中科院分区：
文献类型：
--
作者：
Chae SY;Kim TH;Park K;Jin CH;Son S;Lee S;Youn YS;Kim K;Jo DG;Kwon IC;Chen X;Lee KC
肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）由于其肿瘤细胞特异性的细胞毒性而被认为是一种有吸引力的抗癌剂。然而，其低稳定性、低溶解度、意想不到的副作用和弱的药代动力学特征限制了其成功的临床应用。为了开发基于TRAIL的有效的抗癌生物治疗药物，通过引入三聚体形成拉链序列（HZ-TRAIL）构建了一种新的三聚体TRAIL，然后进行NH 2端特异性聚乙二醇化以产生聚乙二醇化的TRAIL（PEG-HZ-TRAIL）。然后使用各种体外和体内实验研究了PEG-HZ-TRAIL的生物学、物理化学和药学特征，包括基于细胞的细胞毒性测试、溶解度测试、药代动力学分析和抗肿瘤功效评估。尽管PEG化后发生轻微的活性损失，但PEG-HZ-TRAIL通过凋亡途径显示出优异的肿瘤细胞特异性细胞毒性作用，而正常细胞毒性可忽略不计。通过PEG化成功地克服了HZ-TRAIL的稳定性和药代动力学问题。此外，体内抗肿瘤试验显示，PEG-HZ-TRAIL治疗增强了肿瘤异种移植动物模型中与HZ-TRAIL相比的治疗潜力，这些增强归因于其更好的药代动力学特性和肿瘤靶向性能。这些结果表明，PEG-HZ-TRAIL给药提供了一种有效的抗肿瘤治疗，其表现出上级肿瘤靶向和更好地抑制肿瘤生长，并建议PEG-HZ-TRAIL应被认为是抗肿瘤生物治疗的潜在候选者。
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.