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

双靶向和微环境响应胶束作为基因传递系统 ， 提高胶质瘤对放疗的敏感性。

• 影响指数: 14.903
• 发表时间: Mar 2019
• 来源期刊: Acta Pharm Sin B
• DOI: 10.1016/j.apsb.2018.12.001
• PMID: 30972284
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 医学
• 作者列表: Jiao X,Yu Y,Meng J,He M,Zhang CJ,Geng W,Ding B,Wang Z,Ding X

关键词: 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

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.

摘要

Dbait是一种小的双链DNA分子，已被用作放射增敏剂以增强神经胶质瘤对放射疗法（RT）的敏感性。然而,没有有效的药物递送系统来有效地克服血脑屏障(BBB)。这项研究的目的是通过使用BBB和神经胶质瘤双靶向和微环境响应胶束（ch-Kn（s-s）R8-An）将Dbait递送到神经胶质瘤中进行RT，开发一种基因递送系统。Angiopep-2可以靶向在脑毛细血管内皮细胞（BCECs）和神经胶质瘤细胞上过度表达的低密度脂蛋白受体相关蛋白1（LRP1）。特别是,由于肿瘤微环境中基质金属蛋白酶2（MMP-2）上调，我们利用MMP-2反应肽作为酶促降解的接头来缀合血管肽-2。结果表明，ch-Kn(s-s)R8-An胶束保持合理的尺寸(80-160nm)，中等分布，交联后平均粒径减小，临界胶束浓度(CMC)低，表面带正电荷。范围从15到40mV。ch-K5(s-s)R8-An/pEGFP在体外显示出较高的基因转染效率,改善神经胶质瘤细胞的摄取和良好的体外和体内生物相容性。此外,ch-K5(s-s)R8-An/Dbait联合RT在体外显著抑制U251细胞的生长。因此，ch-K5（s-s）R8-An/Dbait可能被证明是靶向胶质瘤并增强RT对U251细胞功效的有前途的基因递送系统。