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Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma
Dai ChuanYun1,2; Fu Ya2; Li Biao3,4; Wang YiGuang1; Zhang Xuan1; Wang JianCheng1; Zhang Qiang1
关键词Tumor Necrosis Factor Alpha Pegylation Cathepsin B-sensitive Dipeptide Antitumor Effect
刊名SCIENCE CHINA-LIFE SCIENCES
2011-02-01
DOI10.1007/s11427-010-4124-z
54期:2页:128-138
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biology
研究领域[WOS]Life Sciences & Biomedicine - Other Topics
关键词[WOS]SITE-SPECIFIC PEGYLATION ; PHASE-I ; POLYETHYLENE-GLYCOL ; ANTITUMOR-ACTIVITY ; CANCER-PATIENTS ; INHIBITORS ; DRUG ; ACCUMULATION ; DOXORUBICIN ; TOXICITY
英文摘要

To improve the pharmacological profile of tumor necrosis factor alpha (TNF-alpha), we have synthesized a new PEGylated prodrug, PEG-vcTNF-alpha, using a cathepsin B-sensitive dipeptide (valine-citrulline, vc) to link branched PEG and TNF-alpha. PEG-modified TNF-alpha without the dipeptide linker (PEG-TNF-alpha) and unconjugated TNF-alpha were also tested as controls. It was found for the first time that TNF-alpha released from PEG-vcTNF-alpha was specifically dependent on the presence of cathepsin B. PEG-vcTNF-alpha induced higher cytotoxicity and greater apoptosis against L929 murine fibrosarcoma cells than PEG-TNF-alpha. Reversal of these effects by a cathepsin-B inhibitor confirmed that these effects were mediated by cathepsin B-specific release of TNF-alpha. In vivo pharmacokinetics studies demonstrated that the plasma stability of PEG-vcTNF-alpha was significantly increased compared to TNF-alpha. Finally, the improved anticancer efficacy of PEG-vcTNF-alpha and the distinct activities among the three formulations confirmed the positive contribution of both PEGylation and the dipeptide linkage to the improved drug-like properties of PEG-vcTNF-alpha. The results here indicate that linking proteins and PEG via the cathepsin B-sensitive dipeptide may be a promising strategy for developing protein therapeutics.

语种英语
WOS记录号WOS:000287702200004
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/55834
Collection北京大学药学院
北京大学药学院_药剂学系
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Chongqing Univ Sci & Technol, Dept Biol, Chongqing 401331, Peoples R China
3.Peking Union Med Coll, Beijing 100193, Peoples R China
4.Chinese Acad Med Sci, Inst Med Plant Dev, Beijing 100193, Peoples R China
Recommended Citation
GB/T 7714
Dai ChuanYun,Fu Ya,Li Biao,et al. Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma[J]. SCIENCE CHINA-LIFE SCIENCES,2011,54(2):128-138.
APA Dai ChuanYun.,Fu Ya.,Li Biao.,Wang YiGuang.,Zhang Xuan.,...&Zhang Qiang.(2011).Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma.SCIENCE CHINA-LIFE SCIENCES,54(2),128-138.
MLA Dai ChuanYun,et al."Linkage with cathepsin B-sensitive dipeptide promotes the in vitro and in vivo anticancer activity of PEGylated tumor necrosis factor-alpha (TNF-alpha) against murine fibrosarcoma".SCIENCE CHINA-LIFE SCIENCES 54.2(2011):128-138.
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