Dual-targeting and microenvironment-responsive micelles as a gene delivery system to improve the sensitivity of glioma to radiotherapy.
10.1016/j.apsb.2018.12.001
- Author:
Xiuxiu JIAO
1
;
Yuan YU
2
;
Jianxia MENG
3
;
Mei HE
1
;
Charles Jian ZHANG
4
;
Wenqian GENG
1
;
Baoyue DING
5
;
Zhuo WANG
3
;
Xueying DING
1
Author Information
1. Department of Pharmaceutics, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai 200080, China.
2. Department of Pharmaceutical Sciences, School of Pharmacy, Second Military Medical University, Shanghai 200082, China.
3. Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200082, China.
4. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91768, USA.
5. Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314000, China.
- Publication Type:Journal Article
- Keywords:
ATCC, American Type Culture Collection;
Arg, arginine;
BBB, blood–brain barrier;
BBTB, blood—brain tumor barriers;
CMC, critical micelle concentration;
Cell-penetrating peptides;
DTSSP, 3,3′-dithiobis(sulfosuccinimidylpropionate);
DTT, dithiothreitol;
FBS, fetal bovine serum;
GBM, glioblastoma multiforme;
GSH, glutathione;
Gene delivery;
Glioma-targeting;
KnR8, cholesterol-polylysine-polyarginine peptide, n = 3, 5, 7;
Lys, lysine;
MMP-2, matrix metalloproteinase 2;
MWCO, molecular weight cutoff;
Microenvironment-responsive micelles;
PDI, polydispersity index;
PE, plating efficiency;
PEI, polyethylenimine;
RT, radiotherapy;
Radiosensitizer;
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;
ch-KnR8-An, the non-cross-linked cholesterol-polylysine-polyarginine peptide core-shell polymer micelles modified with angiopep-2, n = 3, 5, 7;
pDNA, plasmid DNA
- From:
Acta Pharmaceutica Sinica B
2019;9(2):381-396
- CountryChina
- Language:English
-
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-K(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-K(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 , improved uptake in glioma cells and good biocompatibility and . In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells . 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.
