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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
Source PublicationINTERNATIONAL JOURNAL OF PHARMACEUTICS
ISSN0378-5173
Volume529Issue:1-2Pages:275-284
Abstract

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.

KeywordPegylation Transferrin Coupling Long-acting Ciliary Neurotrophic Factor Anti-obese
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1016/j.ijpharm.2017.06.074
Indexed BySCI
Language英语
WOS KeywordHuman Growth-hormone ; Drug-delivery ; Body-weight ; Peg Chain ; Obesity ; Proteins ; Pegylation ; Maleimide ; Receptor ; Brain
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
Funding OrganizationNational Natural Science Foundation of China(20976178 ; Ministry of Education(20120181110036) ; Opening Foundation of National Key Laboratory of Biochemical Engineering(2014KF-4) ; 21336010)
WOS IDWOS:000408009200025
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/23208
Collection生化工程国家重点实验室
Affiliation1.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
Recommended Citation
GB/T 7714
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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