Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature

doi:10.1016/j.biomaterials.2016.11.033

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

	Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature
	Chen, Yingzhi 2,4; Zhang, Meng 2,4; Jin, Hongyue 2; Tang, Yisi 3; Wang, Huiyuan2 ; Xu, Qin 3; Li, Yaping2 ; Li, Feng 1; Huang, Yongzhuo2
刊名	BIOMATERIALS
	2017-02
卷号	116 页码:57-68
关键词	Intein-mediated protein ligation (IPL) Protein toxin Trichosanthin Site-specific PEGylation Gelatinase Cell-penetrating peptide
ISSN号	0142-9612
DOI	10.1016/j.biomaterials.2016.11.033
文献子类	Article
英文摘要	Poor tumor-targeted and cytoplasmic delivery is a bottleneck for protein toxin-based cancer therapy. Ideally, a protein toxin drug should remain stealthy in circulation for prolonged half-life and reduced side toxicity, but turn activated at tumor. PEGylation is a solution to achieve the first goal, but creates a hurdle for the second because PEG rejects interaction between the drugs and tumor cells therein. Such PEG dilemma is an unsolved problem in protein delivery. Herein proposed is a concept of turning PEG dilemma into prodrug-like feature. A site-selectively PEGylated, gelatinase-triggered cell-penetrating trichosanthin protein delivery system is developed with three specific aims. The first is to develop an intein-based ligation method for achieving site-specific modification of protein toxins. The second is to develop a prodrug feature that renders protein toxins remaining stealthy in blood for reduced side toxicity and improved EPR effect. The third is to develop a gelatinase activatable cell-penetration strategy for enhanced tumor targeting and cytoplasmic delivery. Of note, site-specific modification is a big challenge in protein drug research, especially for such a complicated, multifunctional protein delivery system. We successfully develop a protocol for constructing a macromolecular prodrug system with intein-mediated ligation synthesis. With an on-column process of purification and intein-mediated cleavage, the site-specific PEGylation then can be readily achieved by conjugation with the activated C-terminus, thus constructing a PEG-capped, cell-penetrating trichosanthin system with a gelatinase-cleavable linker that enables tumor-specific activation of cytoplasmic delivery. It provides a promising method to address the PEG dilemma for enhanced protein drug delivery, and importantly, a facile protocol for site-specific modification of such a class of protein drugs for improving their druggability and industrial translation. (C) 2016 Elsevier Ltd. All rights reserved.
资助项目	973 Program, China[2014CB931900] ; 973 Program, China[2013CB932503] ; NSFC, China[81172996] ; NSFC, China[81373357] ; NSFC, China[81422048] ; NSFC, China[81521005] ; NSFC, China[81673382]
WOS关键词	MOLECULAR-WEIGHT PROTAMINE ; IN-VIVO ; DIRECTED PEGYLATION ; CANCER-THERAPY ; GENE DELIVERY ; TRICHOSANTHIN ; IMMUNOGENICITY ; IMMUNOTOXINS ; TOXIN ; NANOPARTICLES
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000392681100006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275661]
专题	药物制剂研究中心
通讯作者	Huang, Yongzhuo
作者单位	1.Hampton Univ, Sch Pharm, Kittrell Hall RM216, Hampton, VA 23668 USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Hai Ke Rd, Shanghai 201203, Peoples R China; 3.Guangzhou Univ Chinese Med, Inst Trop Med, 12 Ji Chang Rd, Guangzhou 510405, Guangdong, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Chen, Yingzhi,Zhang, Meng,Jin, Hongyue,et al. Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature[J]. BIOMATERIALS,2017,116:57-68.
APA	Chen, Yingzhi.,Zhang, Meng.,Jin, Hongyue.,Tang, Yisi.,Wang, Huiyuan.,...&Huang, Yongzhuo.(2017).Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature.BIOMATERIALS,116,57-68.
MLA	Chen, Yingzhi,et al."Intein-mediated site-specific synthesis of tumor-targeting protein delivery system: Turning PEG dilemma into prodrug-like feature".BIOMATERIALS 116(2017):57-68.