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Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin
Zhang, Chun1,2; Yu, Rong2; Li, Zenglan1; Feng, Cui1; Wang, Qi1; Liu, Yongdong1; Su, Zhiguo1
2017-08-30
发表期刊INTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN0378-5173
卷号529期号:1-2页码:275-284
摘要To overcome the deficiency of rapid elimination from blood, the truncated human recombinant ciliary neurotrophic factor was formulated by site-specific attachment of different-sized PEG-maleimide or by cross-linking with human transferrin through a hetero-bi-functional PEG linker (NHS-PEG5k-MAL). The PEGylated CNTF was purified by a two-step chromatography procedure and the transferrin coupling CNTF conjugate was separated through an elegant protocol. The conjugation site on CNTF was identified by peptide mapping analysis and validated that the linkage of the conjugates was specifically happened to Cys17 residue. Although both PEGylated and transferrin coupling CNTF demonstrated decreased cell based residual activity, markedly enhanced pharmacokinetic behaviors in normal male Sprague-Dawley rats were observed, especially for the PEG40k-CNTF with approximately 58-times improvement compared with the unmodified counterpart. The evaluation of the in vivo potency of body weight-losing was performed with normal male C57BL6 mice and the results revealed that both PEGylation and transferrin coupling could achieve improved therapeutic benefits relative to that of CNTF. Besides, PEG20k/40k-CNTF demonstrated more effective than transferrin coupling CNTF (Tf-PEG5k-CNTF) despite that the later showed preferable pharmacokinetic profile and cell based residual activity compared with PEG20k-CNTF. Weekly subcutaneous administration of PEG40k-CNTF with 0.5 mg/kg and 1.0 mg/kg dose resulted in approximately 35% and 50% decrease in food intake during one interval period of injection, indicating that PEG40k-CNTF is the most potential anti-obese agent for therapeutics. (C) 2017 Elsevier B.V. All rights reserved.
关键词Pegylation Transferrin Coupling Long-acting Ciliary Neurotrophic Factor Anti-obese
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
DOI10.1016/j.ijpharm.2017.06.074
收录类别SCI
语种英语
关键词[WOS]HUMAN GROWTH-HORMONE ; DRUG-DELIVERY ; BODY-WEIGHT ; PEG CHAIN ; OBESITY ; PROTEINS ; PEGYLATION ; MALEIMIDE ; RECEPTOR ; BRAIN
WOS研究方向Pharmacology & Pharmacy
WOS类目Pharmacology & Pharmacy
项目资助者National Natural Science Foundation of China(20976178 ; Ministry of Education(20120181110036) ; Opening Foundation of National Key Laboratory of Biochemical Engineering(2014KF-4) ; 21336010)
WOS记录号WOS:000408009200025
引用统计
文献类型期刊论文
条目标识符http://ir.ipe.ac.cn/handle/122111/23208
专题生化工程国家重点实验室
作者单位1.Chinese Acad Sci, Inst Proc Engn, State Key Lab Biochem Engn, Beijing 100190, Peoples R China
2.Sichuan Univ, West China Sch Pharm, Minist Educ, Key Lab Drug Targeting & Drug Delivery Syst, Chengdu 610041, Sichuan, Peoples R China
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Zhang, Chun,Yu, Rong,Li, Zenglan,et al. Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin[J]. INTERNATIONAL JOURNAL OF PHARMACEUTICS,2017,529(1-2):275-284.
APA Zhang, Chun.,Yu, Rong.,Li, Zenglan.,Feng, Cui.,Wang, Qi.,...&Su, Zhiguo.(2017).Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin.INTERNATIONAL JOURNAL OF PHARMACEUTICS,529(1-2),275-284.
MLA Zhang, Chun,et al."Development of long-acting ciliary neurotrophic factor by site-specific conjugation with different-sized polyethylene glycols and transferrin".INTERNATIONAL JOURNAL OF PHARMACEUTICS 529.1-2(2017):275-284.
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