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Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy

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Acta Pharmaceutica Sinica B 2019年第2期9卷 381-396页

作者： Xiuxiu Jiao Yuan Yu Jianxia Meng Mei He Charles Jian Zhang Wenqian Geng Baoyue Ding Zhuo Wang Xueying Ding Department of Pharmaceutics Shanghai General Hospital Shanghai Jiao Tong University of Medicine Department of Pharmaceutical Sciences School of Pharmacy Second Military Medical University Department of Pharmacy Changhai Hospital Second Military Medical University Department of Pharmaceutical Sciences College of Pharmacy Western University of Health Sciences Department of Pharmaceutics College of Medicine Jiaxing University

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 to40 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.

关键词： glioma-targeting Cell-penetrating peptides Microenvironment-responsive micelles Gene delivery Radiosensitizer

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