Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5 Canada.
Departments of Medical Biophysics, and Radiation Oncology, University of Toronto, Toronto, ON, M4N 3M5 Canada.
Theranostics. 2018 Jan 1;8(2):314-327. doi: 10.7150/thno.19010. eCollection 2018.
High-dose radiotherapy effects are regulated by acute tumour endothelial cell death followed by rapid tumour cell death instead of canonical DNA break damage. Pre-treatment with ultrasound-stimulated microbubbles (USMB) has enabled higher-dose radiation effects with conventional radiation doses. This study aimed to confirm acute and longitudinal relationships between vascular shutdown and tumour cell death following radiation and USMB in a wild type murine fibrosarcoma model using imaging. Tumour xenografts were treated with single radiation doses of 2 or 8 Gy alone, or in combination with low-/high-concentration USMB. Vascular changes and tumour cell death were evaluated at 3, 24 and 72 h following therapy, using high-frequency 3D power Doppler and quantitative ultrasound spectroscopy (QUS) methods, respectively. Staining using end labelling (ISEL) and cluster of differentiation 31 (CD31) of tumour sections were used to assess cell death and vascular distributions, respectively, as gold standard histological methods. Results indicated a decrease in the power Doppler signal of up to 50%, and an increase of more than 5 dBr in cell-death linked QUS parameters at 24 h for tumours treated with combined USMB and radiotherapy. Power Doppler and quantitative ultrasound results were significantly correlated with CD31 and ISEL staining results (p < 0.05), respectively. Moreover, a relationship was found between ultrasound power Doppler and QUS results, as well as between micro-vascular densities (CD31) and the percentage of cell death (ISEL) (R 0.5-0.9). This study demonstrated, for the first time, the link between acute vascular shutdown and acute tumour cell death using longitudinal imaging, contributing to the development of theoretical models that incorporate vascular effects in radiation therapy. Overall, this study paves the way for theranostic use of ultrasound in radiation oncology as a diagnostic modality to characterize vascular and tumour response effects simultaneously, as well as a therapeutic modality to complement radiation therapy.
高剂量放疗的效果受急性肿瘤内皮细胞死亡的调节，随后是快速的肿瘤细胞死亡，而不是典型的 DNA 断裂损伤。超声刺激微泡（USMB）预处理使常规剂量的辐射具有更高的剂量效果。本研究旨在使用成像技术，在野生型鼠纤维肉瘤模型中确认放疗和 USMB 后血管关闭和肿瘤细胞死亡的急性和纵向关系。肿瘤异种移植物单独接受 2 或 8 Gy 的单次辐射剂量，或与低/高浓度 USMB 联合治疗。在治疗后 3、24 和 72 小时，分别使用高频 3D 功率多普勒和定量超声光谱（QUS）方法评估血管变化和肿瘤细胞死亡。使用末端标记（ISEL）和分化簇 31（CD31）染色的肿瘤切片分别评估细胞死亡和血管分布，作为金标准组织学方法。结果表明，在接受联合 USMB 和放疗的肿瘤中，24 小时时，功率多普勒信号降低了高达 50%，与细胞死亡相关的 QUS 参数增加了超过 5 dBr。功率多普勒和定量超声结果与 CD31 和 ISEL 染色结果显著相关（p < 0.05），分别。此外，还发现了超声功率多普勒和 QUS 结果之间，以及微血管密度（CD31）和细胞死亡百分比（ISEL）之间的关系（R 0.5-0.9）。本研究首次使用纵向成像技术，在理论模型中纳入了血管效应，证明了急性血管关闭与急性肿瘤细胞死亡之间的联系，该模型为放射治疗提供了理论依据。总的来说，这项研究为超声在放射肿瘤学中的治疗应用铺平了道路，使其成为一种同时对血管和肿瘤反应效应进行特征描述的诊断模态，以及一种补充放射治疗的治疗模态。
