Original Articles
Xiuxiu Jiao, Yuan Yu, Jianxia Meng, Mei He, Charles Jian Zhang, Wenqian Geng, Baoyue Ding, Zhuo Wang, Xueying Ding. Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy[J]. Acta Pharmaceutica Sinica B, 2019, 9(2): 381-396

Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy
Xiuxiu Jiaoa, Yuan Yuc, Jianxia Mengd, Mei Hea, Charles Jian Zhange, Wenqian Genga, Baoyue Dingb, Zhuo Wangd, Xueying Dinga
a Department of Pharmaceutics, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai 200080, China;
b Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314000, China;
c Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, Shanghai 200082, China;
d Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200082, China;
e Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91768, USA
Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the blood-brain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-Kn(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-Kn(s-s)R8-An micelles maintained a reasonable size (80-160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency in vitro, improved uptake in glioma cells and good biocompatibility in vitro and in vivo. In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells in vitro. Thus, ch-K5(s-s) R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
Key words:    Glioma-targeting    Cell-penetrating peptides    Microenvironmentresponsive micelles    Gene delivery    Radiosensitizer   
Received: 2018-09-18     Revised: 2018-11-12
DOI: 10.1016/j.apsb.2018.12.001
Funds: We acknowledge the financial support received from the National Natural Science Foundation of China (No.81472349,81302714 and 81201809,China);the Natural Science Foundation of Shanghai (No.14ZR1433300,China);the Interdisciplinary Program of Shanghai Jiao Tong University (No.0507N17014,China);the Innovation Program of Shanghai Municipal Education Commission (No.15ZZ041,China);Natural Science Foundation of Zhejiang Province (No.LQ12H30005,China);and the Public Welfare Technology Application Research Project (No.LGF18H160034,China).
Corresponding author: Baoyue Ding, Zhuo Wang, Xueying Ding     Email:lena_310@163.com;wangzhuo@smmu.edu.cn;dingxueying@126.com
Author description:
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Xiuxiu Jiao
Yuan Yu
Jianxia Meng
Mei He
Charles Jian Zhang
Wenqian Geng
Baoyue Ding
Zhuo Wang
Xueying Ding

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