Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles.
Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles.
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DOI：
10.1007/s11060-015-1807-0
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Hadjipanayis, Costas G.
中科院分区：
文献类型：
--
作者：
Bouras, Alexandros;Kaluzova, Milota;Hadjipanayis, Costas G.
关键词：
已知表皮生长因子受体缺失变体 EGFRvIII 在部分胶质母细胞瘤 (GBM) 肿瘤患者中表达，可增强致瘤性并导致放射和化疗耐药。针对 EGFRvIII 缺失突变体可能会改善 GBM 治疗并改善患者预后。多功能磁性纳米粒子作为一种潜在的临床工具，可以提供癌细胞靶向药物输送、成像和治疗。我们之前的研究表明，EGFRvIII 特异性抗体和西妥昔单抗（EGFR 和 EGFRvIII 特异性抗体）与 IONP（分别为 EGFRvIII-IONP 或西妥昔单抗-IONP）生物缀合时，可以同时通过磁共振成像（MRI）提供灵敏的癌细胞检测和实验性 GBM 的靶向治疗。在这项研究中，我们研究了西妥昔单抗-IONP 是否还可以增强 GBM 的放射敏感性。西妥昔单抗-IONP 与单次 (10Gy x 1) 或多次 (10Gy x 2) 电离辐射 (IR) 联合使用，在对流增强递送 (CED) 后在体外和体内对 EGFRvIII 过表达的人 GBM 细胞进行放射增敏。用西妥昔单抗-IONP 治疗以及随后的单次或分次 IR 治疗后，在体外观察到显着的 GBM 抗肿瘤作用。经过西妥昔单抗-IONP CED 和随后的分级 IR 治疗后，发现植入人 GBM 异种移植物的裸鼠的总体存活率显着增加。 DNA 双链断裂 (DSB) 的增加以及活性氧 (ROS) 形成的增加被认为代表了 IR 和西妥昔单抗-IONP 联合治疗所观察到的放射增敏效应的中介因素。
The epidermal growth factor receptor deletion variant EGFRvIII is known to be expressed in a subset of patients with glioblastoma (GBM) tumors that enhances tumorigenicity and also accounts for radiation and chemotherapy resistance. Targeting the EGFRvIII deletion mutant may lead to improved GBM therapy and better patient prognosis. Multifunctional magnetic nanoparticles serve as a potential clinical tool that can provide cancer cell targeted drug delivery, imaging, and therapy. Our previous studies have shown that an EGFRvIII-specific antibody and cetuximab (an EGFR- and EGFRvIII-specific antibody), when bioconjugated to IONPs (EGFRvIII-IONPs or cetuximab-IONPs respectively), can simultaneously provide sensitive cancer cell detection by magnetic resonance imaging (MRI) and targeted therapy of experimental GBM. In this study, we investigated whether cetuximab-IONPs can additionally allow for the radiosensitivity enhancement of GBM. Cetuximab-IONPs were used in combination with single (10Gy x 1) or multiple fractions (10Gy x 2) of ionizing radiation (IR) for radiosensitization of EGFRvIII-overexpressing human GBM cells in vitro and in vivo after convection-enhanced delivery (CED). A significant GBM antitumor effect was observed in vitro after treatment with cetuximab-IONPs and subsequent single or fractionated IR. A significant increase in overall survival of nude mice implanted with human GBM xenografts was found after treatment by cetuximab-IONP CED and subsequent fractionated IR. Increased DNA double strands breaks (DSBs), as well as increased reactive oxygen species (ROS) formation, were felt to represent the mediators of the observed radiosensitization effect with the combination therapy of IR and cetuximab-IONPs treatment.
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