The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer. METHODS A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time. RESULTS All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01). CONCLUSIONS Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.

中文翻译：

---

碘油在VX2兔肝肿瘤模型中的经动脉化学栓塞治疗学应用。

这项研究的目的是研究脂肪碘作为一种肿瘤特异性成像生物标志物的作用，以确定cTACE的治疗效果，并在肝癌动物模型中使用放射病理学相关性研究其与肿瘤灌注的相互依赖性。方法共有N = 36只兔植入VX2肿瘤的肝脏左叶，使用悬浮在Lipiodol中的阿霉素对cTACE进行治疗，并在TACE后24 h，7天或20天随机处死。未增强和对比增强的CT扫描（包括灌注方案）在cTACE之前和处死之前获得。使用3D定量评估工具并测量动脉血流，门脉血流和灌注指数（PI），对肿瘤和肝组织（非靶标沉积物）中的肿瘤血管形成和碘油沉积进行定量。处死后，对肿瘤和肝脏样品进行组织学染色，包括苏木精和曙红（H＆E），CD31和油红O（ORO），以评估随时间推移的坏死，微血管密度（MVD）和碘油滞留。进行透射电子显微镜（TEM）评估随时间推移的碘油沉积和清除率。结果除一项被排除在进一步分析之外，所有cTACE程序均成功进行。TACE后二十四小时，肿瘤PI（p = 0.04）显着降低，维持在7天（p = 0.003），而不是20天（p = 0.4）。在基线时增强的肿瘤组织的体积与TACE后的Lipiodol阳性肿瘤体积之间存在很强的相关性（R2 = 0.894）。ORO和TEM均显示Lipiodol在VX2肿瘤内的所有成像时间点上均沉积。然而，随着时间的推移，在非肿瘤性肝脏中观察到了渐进的，最终接近完全的碘吡醇洗脱。TACE后24小时至7天之间，MVD降低，而TACE后20天，MVD升高（均p <0.01）。结论我们的数据为脂碘醇作为经皮的，肿瘤特异性的药物递送剂的功能提供了放射学-病理学证据，因为它既可成像又可寻找肿瘤，因此它优先被肿瘤细胞吸收和保留。这些肿瘤特异性功能还使Lipiodol能够充当cTACE治疗功效的成像生物标志物。结合CT上肿瘤血管形成的体积定量，Lipiodol可用作预测患者对cTACE反应的指标，并有助于肝癌患者的治疗管理。随着时间的推移，在非肿瘤肝中观察到逐渐的，最终接近完全的脂质碘醇洗脱。TACE后24小时至7天之间，MVD降低，而TACE后20天，MVD升高（均p <0.01）。结论我们的数据为脂碘醇作为经皮的，肿瘤特异性的药物递送剂的功能提供了放射学-病理学证据，因为它既可成像又可寻找肿瘤，因此它优先被肿瘤细胞吸收和保留。这些肿瘤特异性功能还使Lipiodol能够充当cTACE治疗功效的成像生物标志物。结合CT上肿瘤血管形成的体积定量，Lipiodol可用作预测患者对cTACE反应的指标，并有助于肝癌患者的治疗管理。随着时间的推移，在非肿瘤肝中观察到逐渐的，最终接近完全的脂质碘醇洗脱。TACE后24小时至7天之间，MVD降低，而TACE后20天，MVD升高（均p <0.01）。结论我们的数据为脂碘醇作为经皮的，肿瘤特异性的药物递送剂的功能提供了放射学-病理学证据，因为它既可成像又可寻找肿瘤，因此它优先被肿瘤细胞吸收和保留。这些肿瘤特异性功能还使Lipiodol能够充当cTACE治疗功效的成像生物标志物。结合CT上肿瘤血管形成的体积定量，Lipiodol可用作预测患者对cTACE反应的指标，并有助于肝癌患者的治疗管理。