摘要
Abstract
Radioresistance is a critical challenge limiting the clinical efficacy of radiotherapy for glioblastoma.This study aims to investigate the specific metabolic mechanisms underlying the radiosensitizing effect of the biomimetic nanodrug plasma membrane-coated nanoparticle(self-defined abbreviation:NPPM)on U87 MG human glioblastoma cells using untargeted metabolomics.U87 MG cells were randomly divided into four groups:negative control(NC),NPPM only(NP),irradiation only(IR),and combined treatment(NP_IR).Metabolic profiles were acquired using liquid chromatography-tandem mass spectrometry.Multivariate statistical analyses,including Principal Component Analysis and Orthogonal Partial Least Squares Discriminant Analysis,were employed to identify differential metabolites,followed by KEGG pathway enrichment analysis.The metabolomic profiling revealed that NPPM induced significant metabolic reprogramming in irradiated cells.Specifically,NPPM triggered an intense arachidonic acid cascade storm,characterized by substantial consumption of the substrate arachidonic acid and a dramatic upregulation of the lipid peroxidation marker 20-Oxo-Leukotriene E4.Simultaneously,NPPM specifically blocked the purine salvage pathway,resulting in the abnormal accumulation of the precursor guanosine and the significant depletion of deoxyribose 5-phosphate,a key raw material for DNA repair.Furthermore,comparison between the NP and NP_IR groups revealed that the combined treatment specifically caused a significant decrease in the antioxidant coenzyme pyridoxine,indicating excessive consumption of antioxidant reserves.Moreover,the malondialdehyde assay confirmed that the combined treatment induced significantly higher membrane lipid oxidative damage compared to monotherapy.In conclusion,by driving lipid peroxidation and blocking nucleotide synthesis,NPPM primes U87 MG cells into a metabolically vulnerable state,where radiation-induced oxidative stress exceeds the cellular threshold,ultimately triggering antioxidant system collapse and cell death.关键词
放射敏感性/放射疗法/纳米颗粒/代谢组学/胶质母细胞瘤Key words
Radiosensitivity/Radiotherapy/Nanoparticle/Metabolomics/Glioblastoma分类
医药卫生
