High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA

doi:10.7150/thno.19863

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	High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA
	Ye, Junxiao 2,3; Liu, Ergang 2,3; Gong, Junbo 3; Wang, Jianxin 4,5,6; Huang, Yongzhuo7 ; He, Huining 2; Yang, Victor C.1,2
刊名	THERANOSTICS
	2017
卷号	7 期号:9 页码:2495-2508
关键词	cell penetrating peptide siRNA delivery covalent CPP-siRNA chemical conjugate mass preparation
ISSN号	1838-7640
DOI	10.7150/thno.19863
文献子类	Article
英文摘要	Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice. Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications. With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides. However, construction of such a chemical conjugate has been referred by scientists in this field as the "Holy Grail" challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds. Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates. Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities. This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation. To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.
资助项目	National Natural Science Foundation of China (NSFC)[81402856] ; National Natural Science Foundation of China (NSFC)[81361140344] ; National Key Research and Development Plan[2016YFE0119200] ; Tianjin Municipal Science and Technology Commission[15JCYBJC28700] ; National Key Basic Research Program of China[2013CB932502]
WOS关键词	CELL-PENETRATING PEPTIDES ; MOLECULAR-WEIGHT PROTAMINE ; MEDIATED INTRACELLULAR DELIVERY ; MALDI MASS-SPECTROMETRY ; DRUG-DELIVERY ; RAMAN-SPECTROSCOPY ; IN-VITRO ; STRATEGY ; DIFFERENTIATION ; NANOPARTICLES
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000404024500005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275711]
专题	药物制剂研究中心
通讯作者	He, Huining; Yang, Victor C.
作者单位	1.Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA 2.Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China; 3.Tianjin Univ, Collaborat Innovat Ctr Chem Sci & Chem Engn & Tec, Tianjin 300072, Peoples R China; 4.Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201201, Peoples R China; 5.Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201201, Peoples R China; 6.PLA, Shanghai 201201, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Ye, Junxiao,Liu, Ergang,Gong, Junbo,et al. High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA[J]. THERANOSTICS,2017,7(9):2495-2508.
APA	Ye, Junxiao.,Liu, Ergang.,Gong, Junbo.,Wang, Jianxin.,Huang, Yongzhuo.,...&Yang, Victor C..(2017).High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA.THERANOSTICS,7(9),2495-2508.
MLA	Ye, Junxiao,et al."High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA".THERANOSTICS 7.9(2017):2495-2508.