Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites

doi:10.1016/j.biomaterials.2017.12.018

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

	Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites
	Xu, Fan 1,5; Zhong, Huihai 2,5; Chang, Ya 1,5; Li, Dongdong 1,5; Jin, Hongyue 5; Zhang, Meng 5; Wang, Huiyuan5 ; Jiang, Chen 4; Shen, Youqing 3; Huang, Yongzhuo5
刊名	BIOMATERIALS
	2018-03
卷号	158 页码:56-73
关键词	TRAIL Gene delivery Monensin Poly-gamma-glutamic acid Death receptor Drug resistance
ISSN号	0142-9612
DOI	10.1016/j.biomaterials.2017.12.018
文献子类	Article
英文摘要	Chemoresistance remains a formidable hurdle against cancer therapy. Seeking for novel therapy strategies is an urgent need for those who no longer benefit from chemotherapy. Chemoresistance is usually associated with the dysfunction of intrinsic apoptosis. Targeting extrinsic apoptosis via TRAIL signaling and the death receptors could be a potential solution to treat chemoresistant cancer. A highly biocom-patible nano system for codelivery of the TRAIL DNA and the death receptor sensitizer monensin was developed, in which low-molecular-weight PEI (LMW-PEI) was crosslinked by the sulfhydryl cyclodextrin via disulfide bonds, and then bound with DNA, thus forming the bioreducible polyplex cores. In addition, the cyclodextrin also functioned as a carrier for the hydrophobic monensin via host-guest inclusion. Poly-gamma-glutamic acid (gamma-PGA) was used to modify the polyplex core via charge interaction. The gamma-PGA corona can specifically bind with the tumor-associated gamma-glutamyl transpeptidase (GGT) overexpressed on the tumor cells, and achieve tumor-targeting delivery. Moreover, the tumor-homing peptide RGD-modified gamma-PGA was also prepared as the surface coating materials for further improving gene delivery efficiency. This gene delivery system was characterized by the dual ligand-targeting, dual stimuli responsive features. The ligands of RGD and gamma-PGA can target the tumor-associated receptors (i.e., integrin and GGT). The conformation of gamma-PGA is pH-sensitive, and the tumor acidic micro environments could trigger the detachment of surface-coating gamma-PGA. The disulfide crosslinking LMW-PEI is redox-sensitive, and its fast disassembling in the tumor cells could favor the efficient gene delivery. The anti-tumor efficacy was demonstrated both in vitro and in vivo. Moreover, MYC-mediated synthetic lethality could be an important mechanism for overcoming the drug resistance. An important finding of our studies is the demonstration of the in vivo treatment efficacy of TRAIL/monensin, thus providing a potential novel therapeutic strategy for overcoming drug-resistant cancer. (C) 2018 Elsevier Ltd. All rights reserved.
资助项目	National Basic Research Program of China (973 Program)[2014CB931900] ; National Basic Research Program of China (973 Program)[2013CB932503] ; NSFC, China[81373357] ; NSFC, China[81422048] ; NSFC, China[81673382] ; NSFC, China[81402883] ; NSFC, China[81521005] ; Fudan-SIMM Joint Research Fund[FU-SIMM20174009] ; Scientific Research and Equipment Development Project[YZ201437] ; Youth Innovation Promotion Association[00000000]
WOS关键词	IN-VIVO ; COLON-CANCER ; TRAIL RESISTANCE ; GENE DELIVERY ; UP-REGULATION ; APOPTOSIS ; CELLS ; REVERSAL ; NANOPARTICLES ; SENSITIZATION
WOS研究方向	Engineering ; Materials Science
语种	英语
出版者	ELSEVIER SCI LTD
WOS记录号	WOS:000424186100006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279885]
专题	药物制剂研究中心
通讯作者	Huang, Yongzhuo
作者单位	1.Univ Sci & Technol China, Nano Scitech Inst, Suzhou 215123, Peoples R China; 2.Shanghai Univ, Coll Sci, Shanghai 200444, Peoples R China; 3.Zhejiang Univ, Coll Chem & Biol Engn, Hangzhou 310027, Peoples R China 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xu, Fan,Zhong, Huihai,Chang, Ya,et al. Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites[J]. BIOMATERIALS,2018,158:56-73.
APA	Xu, Fan.,Zhong, Huihai.,Chang, Ya.,Li, Dongdong.,Jin, Hongyue.,...&Huang, Yongzhuo.(2018).Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites.BIOMATERIALS,158,56-73.
MLA	Xu, Fan,et al."Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites".BIOMATERIALS 158(2018):56-73.