Procissi Daniele, Jannetti Stephen A, Zannikou Markella, Zhou Zhengyuan, McDougald Darryl, Kanojia Deepak, Zhang Hui, Burdett Kirsten, Vaidyanathan Ganesan, Zalutsky Michael R, Balyasnikova Irina V
Department of Neurological Surgery, Northwestern University, Chicago, Illinois, USA.
Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA.
Neurooncol Adv. 2022 Aug 23;4(1):vdac135. doi: 10.1093/noajnl/vdac135. eCollection 2022 Jan-Dec.
Single-domain antibody fragments (aka VH, ~ 13 kDa) are promising delivery systems for brain tumor theranostics; however, achieving efficient delivery of VH to intracranial lesions remains challenging due to the tumor-brain barrier. Here, we evaluate low-dose whole-brain irradiation as a strategy to increase the delivery of an anti- human epidermal growth factor receptor type 2 (HER2) VH to breast cancer-derived intracranial tumors in mice.
Mice with intracranial HER2-positive BT474BrM3 tumors received 10-Gy fractionated cranial irradiation and were evaluated by noninvasive imaging. Anti-HER2 VH 5F7 was labeled with F, administered intravenously to irradiated mice and controls, and PET/CT imaging was conducted periodically after irradiation. Tumor uptake of F-labeled 5F7 in irradiated and control mice was compared by PET/CT image analysis and correlated with tumor volumes. In addition, longitudinal dynamic contrast-enhanced MRI (DCE-MRI) was conducted to visualize and quantify the potential effects of radiation on tumor perfusion and permeability.
Increased F-labeled 5F7 intracranial tumor uptake was observed with PET in mice receiving cranial irradiation, with maximum tumor accumulation seen approximately 12 days post initial radiation treatment. No radiation-induced changes in HER2 expression were detected by Western blot, flow cytometry, or on tissue sections. DCE-MRI imaging demonstrated transiently increased tumor perfusion and permeability after irradiation, consistent with the higher tumor uptake of F-labeled anti-HER2 5F7 in irradiated mice.
Low-level brain irradiation induces dynamic changes in tumor vasculature that increase the intracranial tumor delivery of an anti-HER2 VH, which could facilitate the use of radiolabeled VH to detect, monitor, and treat HER2-expressing brain metastases.
单域抗体片段（即VH，约13 kDa）是用于脑肿瘤诊疗的有前景的递送系统；然而，由于肿瘤-脑屏障，实现VH向颅内病变的有效递送仍然具有挑战性。在此，我们评估低剂量全脑照射作为一种策略，以增加抗人表皮生长因子受体2（HER2）VH向小鼠乳腺癌来源的颅内肿瘤的递送。
患有颅内HER2阳性BT474BrM3肿瘤的小鼠接受10 Gy分次颅脑照射，并通过无创成像进行评估。抗HER2 VH 5F7用氟标记，静脉注射给照射后的小鼠和对照组，并在照射后定期进行PET/CT成像。通过PET/CT图像分析比较照射组和对照组小鼠中氟标记的5F7的肿瘤摄取情况，并与肿瘤体积相关联。此外，进行纵向动态对比增强MRI（DCE-MRI）以可视化和量化辐射对肿瘤灌注和通透性的潜在影响。
在接受颅脑照射的小鼠中，PET观察到氟标记的5F7在颅内肿瘤的摄取增加，在初始放射治疗后约12天观察到最大肿瘤蓄积。通过蛋白质印迹、流式细胞术或组织切片未检测到辐射诱导的HER2表达变化。DCE-MRI成像显示照射后肿瘤灌注和通透性短暂增加，这与照射小鼠中氟标记的抗HER2 5F7的较高肿瘤摄取一致。
低水平脑照射诱导肿瘤血管的动态变化，增加抗HER2 VH向颅内肿瘤的递送，这可能有助于使用放射性标记的VH来检测、监测和治疗表达HER2的脑转移瘤。
