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。
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.
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