Improved method for synthesis of low molecular weight protamine-siRNA conjugate

doi:10.1016/j.apsb.2017.11.011

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	Improved method for synthesis of low molecular weight protamine-siRNA conjugate
	Yu, Zhili 5; Ye, Junxiao 6; Pei, Xing 5; Sun, Lu 5; Liu, Ergang 7; Wang, Jianxin 1,2,8; Huang, Yongzhuo3 ; Lee, Seung Jin 4; He, Huining 5
刊名	ACTA PHARMACEUTICA SINICA B
	2018-01
卷号	8 期号:1 页码:116-126
关键词	Cell penetrating peptide siRNA Conjugate Conjugation yield Biomimetic delivery Crosslinker
ISSN号	2211-3835
DOI	10.1016/j.apsb.2017.11.011
文献子类	Article
英文摘要	RNAi technology has aroused wide public interest due to its high efficiency and specificity to treat multiple types of diseases. However, the effective delivery of siRNA remains a challenge due to its large molecular weight and strong anionic charge. Considering their remarkable functions in vivo and features that are often desired in drug delivery carriers, biomimetic systems for siRNA delivery become an effective and promising strategy. Based on this, covalent attachment of synthetic cell penetrating peptides (CPP) to siRNA has become of great interest. We developed a monomeric covalent conjugate of low molecular weight protamine (LMWP, a well-established CPP) and siRNA via a cytosol-cleavable disulfide linkage using PEG as a crosslinker. Results showed that the conjugates didn't generate coagulation, and exhibited much better RNAi potency and intracellular delivery compared with the conventional charge-complexed CPP/siRNA aggregates. Three different synthetic and purification methods were compared in order to optimize synthesis efficiency and product yield. The methodology using hetero-bifunctional NHS-PEG-OPSS as a crosslinker to synthesize LMWP siRNA simplified the synthesis and purification process and produced the highest yield. These results pave the way towards siRNA biomimetic delivery and future clinical translation. (C) 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
资助项目	National Key Research and Development Plan[2016YFE0119200] ; National Natural Science Foundation of China (NSFC)[81402856] ; National Natural Science Foundation of China (NSFC)[81361140344] ; Tianjin Municipal Science and Technology Commission[15JCYBJC28700] ; National Key Basic Research Program of China[2013CB932502]
WOS关键词	CELL-PENETRATING PEPTIDE ; SMALL INTERFERING RNA ; DRUG-DELIVERY ; TARGETED DELIVERY ; THERAPEUTICS ; EFFICIENT ; SYSTEMS ; NANOCOMPLEXES ; NANOPARTICLES ; NANOVECTOR
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000426437100013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272325]
专题	药物制剂研究中心
通讯作者	He, Huining
作者单位	1.Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201201, Peoples R China; 2.Fudan Univ, Minist Educ, Sch Pharm, Dept Pharmaceut, Shanghai 201201, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 4.Ewha Womans Univ, Dept Pharm, Seoul 120750, South Korea 5.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China; 6.Tsinghua Univ, Coll Pharm, Beijing 100084, Peoples R China; 7.Tianjin Univ, Collaborat Innovat Ctr Chem Sci & Chem Engn & Tec, Tianjin 300072, Peoples R China; 8.PLA, Shanghai 201201, Peoples R China;
推荐引用方式 GB/T 7714	Yu, Zhili,Ye, Junxiao,Pei, Xing,et al. Improved method for synthesis of low molecular weight protamine-siRNA conjugate[J]. ACTA PHARMACEUTICA SINICA B,2018,8(1):116-126.
APA	Yu, Zhili.,Ye, Junxiao.,Pei, Xing.,Sun, Lu.,Liu, Ergang.,...&He, Huining.(2018).Improved method for synthesis of low molecular weight protamine-siRNA conjugate.ACTA PHARMACEUTICA SINICA B,8(1),116-126.
MLA	Yu, Zhili,et al."Improved method for synthesis of low molecular weight protamine-siRNA conjugate".ACTA PHARMACEUTICA SINICA B 8.1(2018):116-126.