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学科主题: 药学
题名:
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
作者: 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
发表日期: 2011-02-01
DOI: 10.1007/s11427-010-4124-z
卷: 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
所属项目编号: 2007AA021811 ; 30701055 ; 20070410029
项目资助者: National High Technology Research and Development Program of China ; National Natural Science Foundation of China ; Postdoctoral Science Foundation of China
WOS记录号: WOS:000287702200004
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/55834
Appears in Collections:北京大学药学院_期刊论文

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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:
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.
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