1. Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy
- Author
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Xiuxiu Jiao, Baoyue Ding, He Mei, Wenqian Geng, Jianxia Meng, Charles J Zhang, Yuan Yu, Xueying Ding, and Zhuo Wang
- Subjects
PEI, polyethylenimine ,Original article ,Radiosensitizer ,MWCO, molecular weight cutoff ,Microenvironment-responsive micelles ,RT, radiotherapy ,Gene delivery ,PE, plating efficiency ,ch-Kn(s-s)R8-An, the disulfide cross-linked cholesterol-polylysine-polyarginine peptide core-shell polymer micelles modified with angiopep-2, n = 3, 5, 7 ,03 medical and health sciences ,0302 clinical medicine ,FBS, fetal bovine serum ,In vivo ,Glioma ,Glioma-targeting ,GSH, glutathione ,medicine ,MMP-2, matrix metalloproteinase 2 ,General Pharmacology, Toxicology and Pharmaceutics ,BBB, blood–brain barrier ,030304 developmental biology ,Arg, arginine ,0303 health sciences ,Tumor microenvironment ,ATCC, American Type Culture Collection ,Chemistry ,lcsh:RM1-950 ,CMC, critical micelle concentration ,ch-KnR8-An, the non-cross-linked cholesterol-polylysine-polyarginine peptide core-shell polymer micelles modified with angiopep-2, n = 3, 5, 7 ,Cell-penetrating peptides ,PDI, polydispersity index ,pDNA, plasmid DNA ,Transfection ,GBM, glioblastoma multiforme ,medicine.disease ,LRP1 ,lcsh:Therapeutics. Pharmacology ,DTT, dithiothreitol ,030220 oncology & carcinogenesis ,Drug delivery ,Cancer research ,KnR8, cholesterol-polylysine-polyarginine peptide, n = 3, 5, 7 ,DTSSP, 3,3′-dithiobis(sulfosuccinimidylpropionate) ,BBTB, blood—brain tumor barriers ,Lys, lysine - Abstract
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., Graphical abstract Using Dbait as a radiosensitizer, dual-targeting and microenvironment-responsive micelle is developed as a gene delivery system to improve sensitivity of glioma to radiotherapy (RT). The micelle can effectively target glioma and further penetrate into the core of the tumor through exposing R8 to deliver Dbait into glioma cells.fx1
- Published
- 2019