Department of Biomedical Engineering, Biomedical NMR, Eindhoven, the Netherlands.
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Cancer Res. 2018 Mar 15;78(6):1561-1570. doi: 10.1158/0008-5472.CAN-17-2569. Epub 2018 Jan 9.
Dynamic contrast-enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to antivascular therapies. Multiagent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we used multiagent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multiagent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 and 24 hours after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was used to estimate flow F, blood volume fraction , mean capillary transit time , bolus arrival time , extracellular extravascular fraction , vascular heterogeneity index α (all identical between agents) and extraction fraction E (reflective of permeability), and transfer constant (both agent-specific) in perfused pixels. F, , and α decreased at both time points after DMXAA, whereas t increased. E (G2 and G5) showed an initial increase, after which, both parameters restored. (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, , and Gd-DOTA showed significant changes. Histologic perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multiagent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy by separating simultaneous changes in tumor hemodynamics and vascular permeability. These findings describe a new approach to measure separately the effects of antivascular therapy on tumor hemodynamics and vascular permeability, which could help more rapidly and accurately assess the efficacy of experimental therapy of this class. .
动态对比增强磁共振成像（DCE-MRI）是一种很有前途的技术，可用于评估肿瘤血管对血管靶向治疗的反应。多试剂 DCE-MRI 采用低和高分子量对比剂的组合，这可能会提高肿瘤血流动力学和血管通透性参数估计的准确性。在这项研究中，我们使用多试剂 DCE-MRI 来评估血管破坏治疗后肿瘤血流动力学和血管通透性的变化。在给予血管破坏剂 DMXAA 或安慰剂之前、之后 2 小时和 24 小时，在荷瘤小鼠中进行多试剂 DCE-MRI（依次注射 G5 树枝状大分子、G2 树枝状大分子和 Gd-DOTA）。受约束的 DCE-MRI 伽马毛细血管渡越时间模型用于估计流量 F、血容量分数 、平均毛细血管渡越时间 t、对比剂到达时间 t、细胞外细胞外分数 、血管异质性指数 α（所有试剂均相同）和提取分数 E（反映通透性）以及转移常数 （均为试剂特异性）在灌注像素中。在 DMXAA 后，F、和α在两个时间点都降低，而 t 增加。E（G2 和 G5）最初增加，然后这两个参数都恢复。G2 和 Gd-DOTA 在治疗后两个时间点均降低。在对照、安慰剂治疗的动物中，只有 F、和 Gd-DOTA 显示出显著变化。DMXAA 治疗组的肿瘤组织灌注分数明显低于对照组。我们的结果表明，多试剂示踪动力学模型如何通过分离肿瘤血流动力学和血管通透性的同时变化，准确地确定血管破坏治疗的效果。这些发现描述了一种新的方法，可以单独测量抗血管生成治疗对肿瘤血流动力学和血管通透性的影响，这有助于更快速和准确地评估此类实验治疗的疗效。
