Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery
文献类型：期刊论文
| 作者 | Chen, Yingzhi1,2; Zhang, Meng1,2; Jin, Hongyue1,2; Li, Dongdong2,3; Xu, Fan2,3; Wu, Aihua2; Wang, Jinyu2; Huang, Yongzhuo2
|
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2017 |
| 卷号 | 7期号:14页码:3489-3503 |
| 关键词 | trichosanthin lactoferrin brain targeted delivery antiglioma therapy MMP-2 intein-mediated protein ligation cell-penetrating peptide |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.20578 |
| 文献子类 | Article |
| 英文摘要 | Malignant glioma is one of the most untreatable cancers because of the formidable blood-brain barrier (BBB), through which few therapeutics can penetrate and reach the tumors. Biologics have been booming in cancer therapy in the past two decades, but their application in brain tumor has long been ignored due to the impermeable nature of BBB against effective delivery of biologics. Indeed, it is a long unsolved problem for brain delivery of macromolecular drugs, which becomes the Holy Grail in medical and pharmaceutical sciences. Even assisting by targeting ligands, protein brain delivery still remains challenging because of the synthesis difficulties of ligand-modified proteins. Herein, we propose a rocket-like, multistage booster delivery system of a protein toxin, trichosanthin (TCS), for antiglioma treatment. TCS is a ribosome-inactivating protein with the potent activity against various solid tumors but lack of specific action and cell penetration ability. To overcome the challenge of its poor druggability and site-specific modification, intein-mediated ligation was applied, by which a gelatinase-cleavable peptide and cell-penetrating peptide (CPP)-fused recombinant TCS toxin can be site-specifically conjugated to lactoferrin (LF), thus constructing a BBB-penetrating, gelatinase-activatable cell-penetrating nanohybrid TCS toxin. This nanohybrid TCS system is featured by the multistage booster strategy for glioma dual-targeting delivery. First, LF can target to the BBB-overexpressing low-density lipoprotein receptor-related protein-1 (LRP-1), and assist with BBB penetration. Second, once reaching the tumor site, the gelatinase-cleavable peptide acts as a separator responsive to the glioma-associated matrix metalloproteinases (MMPs), thus releasing to the CPP-fused toxin. Third, CPP mediates intratumoral and intracellular penetration of TCS toxin, thereby enhancing its antitumor activity. The BBB penetration and MMP-2-activability of this delivery system were demonstrated. The antiglioma activity was evaluated in the subcutaneous and orthotopic animal models. Our work provides a useful protocol for improving the druggability of such class of protein toxins and promoting their in-vivo application for targeted cancer therapy. |
| WOS关键词 | DIRECTED PEGYLATION ; DRUG-DELIVERY ; PRODRUG-LIKE ; TRICHOSANTHIN ; BRAIN ; NANOPARTICLES ; REVERSAL ; CANCER ; IMMUNOGENICITY ; APOPTOSIS |
| 资助项目 | 973 Program, China[2013CB932503] ; 973 Program, China[2014CB931900] ; NSFC, China[81172996] ; NSFC, China[81373357] ; NSFC, China[81422048] ; NSFC, China[81673382] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000407855900007 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275702]  |
| 专题 | 药物制剂研究中心 |
| 通讯作者 | Huang, Yongzhuo |
| 作者单位 | 1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China; 3.Univ Sci & Technol China, Nano Sci & Technol Inst, 166 Ren Ai Rd, Suzhou 215123, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Yingzhi,Zhang, Meng,Jin, Hongyue,et al. Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery[J]. THERANOSTICS,2017,7(14):3489-3503. |
| APA | Chen, Yingzhi.,Zhang, Meng.,Jin, Hongyue.,Li, Dongdong.,Xu, Fan.,...&Huang, Yongzhuo.(2017).Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery.THERANOSTICS,7(14),3489-3503. |
| MLA | Chen, Yingzhi,et al."Glioma Dual-Targeting Nanohybrid Protein Toxin Constructed by Intein-Mediated Site-Specific Ligation for Multistage Booster Delivery".THERANOSTICS 7.14(2017):3489-3503. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。