Mu Ketao, Zhang Shun, Ai Tao, Jiang Jingjing, Yao Yihao, Jiang Lingyu, Zhou Qing, Xiang Hongbing, Zhu Yanhong, Yang Xiangliang, Zhu Wenzhen
Mol Imaging. 2015;14. doi: 10.2310/7290.2015.00002.
The objective of this study was to successfully synthesize epidermal growth factor receptor monoclonal antibody-conjugated superparamagnetic iron oxide nanoparticles (EGFRmAb-SPIONs) and explore their biocompatibility and potential applications as a targeted magnetic resonance imaging (MRI) contrast agent for the EGFR-specific detection of brain glioma in vivo. After conjugation of EGFRmAb with SPIONs, the magnetic characteristics of EGFRmAb-SPIONs were investigated. Thereafter, the targeting abilities of EGFRmAb-SPIONs with MRI were qualitatively and quantitatively assessed in EGFR-positive C6 glioma cells in vitro and in a Wistar rat model bearing C6 glioma in vivo. Furthermore, the preliminary biocompatibility and toxicity of EGFRmAb-SPIONs were evaluated in normal rats through hematology assays and histopathologic analyses. Statistical analysis was performed using one-way analysis of variance and Student t-test, with a significance level of p < .05. From the results of EGFRmAb-SPION characterizations, the average particle size was 10.21 nm and the hydrodynamic diameter was 161.5 ± 2.12 nm. The saturation magnetization was 55 emu/g·Fe, and T2 relaxivity was 92.73 s-1mM-1 in distilled water. The preferential accumulation of the EGFRmAb-SPIONs within glioma and subsequent MRI contrast enhancement were demonstrated both in vitro in C6 cells and in vivo in rats bearing C6 glioma. After intravenous administration of EGFRmAb-SPIONs, T2-weighted MRI of the rat model with brain glioma exhibited an apparent hypointense region within glioma from 2 to 48 hours. The maximal image contrast was reached at 24 hours, where the signal intensity decreased and the R2 value increased by 30% compared to baseline. However, T2-weighted imaging of the rat model administered with SPIONs showed no visible signal changes within the tumor over the same time period. Moreover, no evident toxicities in vitro and in vivo with EGFRmAb-SPIONs were clearly identified based on the laboratory examinations. EGFRmAb-SPIONs could potentially be employed as a targeted contrast agent in the molecule-specific diagnosis of brain glioma in MRI.
本研究的目的是成功合成表皮生长因子受体单克隆抗体偶联超顺磁性氧化铁纳米颗粒（EGFRmAb-SPIONs），并探索其生物相容性以及作为靶向磁共振成像（MRI）造影剂在体内对脑胶质瘤进行EGFR特异性检测的潜在应用。将EGFRmAb与SPIONs偶联后，对EGFRmAb-SPIONs的磁特性进行了研究。此后，在体外EGFR阳性C6胶质瘤细胞以及体内携带C6胶质瘤的Wistar大鼠模型中，对EGFRmAb-SPIONs的MRI靶向能力进行了定性和定量评估。此外，通过血液学检测和组织病理学分析，在正常大鼠中评估了EGFRmAb-SPIONs的初步生物相容性和毒性。采用单因素方差分析和Student t检验进行统计分析，显著性水平为p <.05。从EGFRmAb-SPIONs的表征结果来看，平均粒径为10.21 nm，流体动力学直径为161.5 ± 2.12 nm。饱和磁化强度为55 emu/g·Fe，在蒸馏水中的T2弛豫率为92.73 s-1mM-1。在体外C6细胞和体内携带C6胶质瘤的大鼠中，均证实了EGFRmAb-SPIONs在胶质瘤内的优先聚集以及随后的MRI对比增强。静脉注射EGFRmAb-SPIONs后，脑胶质瘤大鼠模型的T2加权MRI显示，在2至48小时内胶质瘤内出现明显的低信号区。最大图像对比度在24小时达到，此时信号强度降低，R2值比基线增加了30%。然而，在相同时间段内，注射SPIONs的大鼠模型的T2加权成像显示肿瘤内无可见信号变化。此外，根据实验室检查，未明确发现EGFRmAb-SPIONs在体外和体内有明显毒性。EGFRmAb-SPIONs有可能作为靶向造影剂用于MRI对脑胶质瘤的分子特异性诊断。
