Recombinant TAT-gelonin fusion toxin: Synthesis and characterization of heparin/protamine-regulated cell transduction

doi:10.1002/jbm.a.35188

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物制剂研究中心

	Recombinant TAT-gelonin fusion toxin: Synthesis and characterization of heparin/protamine-regulated cell transduction
	Shin, Meong Cheol 1,7; Zhao, Jingwen 3; Zhang, Jian 2,6; Huang, Yongzhuo5 ; He, Huining 7; Wang, Mei 4; Min, Kyoung Ah 1; Yang, Victor C.1,7
刊名	JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
	2015-01
卷号	103 期号:1 页码:409-419
关键词	gelonin TAT heparin protamine tumor
ISSN号	1549-3296
DOI	10.1002/jbm.a.35188
文献子类	Article
英文摘要	Protein toxins, such as gelonin, are highly desirable anti-cancer drug candidates due to their unparalleled potency and repetitive reaction mechanism in inhibiting protein translation. However, for its potential application in cancer therapy, there remains the cell membrane barrier that allows permeation of only small molecules, which must be overcome. To address this challenge, we conjugated gelonin with a protein transduction domain (PTD), the TAT peptide, via genetic recombination. The chimeric TAT-gelonin fusion protein (TAT-Gel) retained equipotent N-glycosidase activity yet displayed greater cell uptake than unmodified recombinant gelonin (rGel), thereby yielding a significantly augmented cytotoxic activity. Remarkably, TAT-Gel displayed up to 177-fold lower IC50 (avg. 54.3 nM) than rGel (avg. IC50: 3640 nM) in tested cell lines. This enhanced cytotoxicity, however, also raised potential toxicity concerns due to the non-selectivity of PTD in its mediated cell transduction. To solve this problem, we investigated the plausibility of regulating the cell transduction of TAT-Gel via a reversible masking using heparin and protamine. Here, we demonstrated, both in vitro and in vivo, that the cell transduction of TAT-Gel can be completely curbed with heparin and yet this heparin block can be efficiently reversed by the addition of protamine. This reversible tight regulation of the cell transduction of TAT-Gel by heparin and protamine sheds light of possible application of TAT-Gel in achieving a highly effective yet safe drug therapy for the treatment of tumors. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 409-419, 2015.
资助项目	NSFC[81361140344] ; National Key Basic Research Program of China[2013CB932502] ; National Institutes of Health[CA114612]
WOS关键词	PENETRATING PEPTIDES ; ASPARAGINASE THERAPY ; CANCER-TREATMENT ; IN-VITRO ; DELIVERY ; PROTEIN ; IMMUNOTOXIN ; CONJUGATION ; ENDOCYTOSIS ; CHALLENGES
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	WILEY
WOS记录号	WOS:000345572100045
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276793]
专题	药物制剂研究中心
通讯作者	Zhao, Jingwen
作者单位	1.Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA; 2.Soochow Univ, Dept Polymer Sci & Engn, Coll Chem Chem Engn & Mat Sci, Biomed Polymers Lab, Suzhou 215123, Peoples R China; 3.Tianjin Univ, Sch Pharmaceut Sci & Technol, Dept Mol & Cellular Pharmacol, Tianjin 300072, Peoples R China; 4.Xinjiang Med Univ, Coll Pharm, Urumqi 830011, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 6.Soochow Univ, Dept Polymer Sci & Engn, Coll Chem Chem Engn & Mat Sci, Jiangsu Key Lab Adv Funct Polymer Design & Applic, Suzhou 215123, Peoples R China; 7.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China;
推荐引用方式 GB/T 7714	Shin, Meong Cheol,Zhao, Jingwen,Zhang, Jian,et al. Recombinant TAT-gelonin fusion toxin: Synthesis and characterization of heparin/protamine-regulated cell transduction[J]. JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A,2015,103(1):409-419.
APA	Shin, Meong Cheol.,Zhao, Jingwen.,Zhang, Jian.,Huang, Yongzhuo.,He, Huining.,...&Yang, Victor C..(2015).Recombinant TAT-gelonin fusion toxin: Synthesis and characterization of heparin/protamine-regulated cell transduction.JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A,103(1),409-419.
MLA	Shin, Meong Cheol,et al."Recombinant TAT-gelonin fusion toxin: Synthesis and characterization of heparin/protamine-regulated cell transduction".JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A 103.1(2015):409-419.