Ultrasound Research Laboratory, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA, 19104, USA.
Penn Image-Guided Interventions Lab, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 646 BRB II/III, Philadelphia, PA, 19104, USA.
Sci Rep. 2021 Jul 30;11(1):15553. doi: 10.1038/s41598-021-94323-0.
This study investigates the use of hydralazine to enhance ultrasound hyperthermia for the treatment of hepatocellular carcinoma (HCC) by minimizing flow-mediated heat loss from the tumor. Murine HCC tumors were treated with a continuous mode ultrasound with or without an intravenous administration of hydralazine (5 mg/kg). Tumor blood flow and blood vessels were evaluated by contrast-enhanced ultrasound (CEUS) imaging and histology, respectively. Hydralazine markedly enhanced ultrasound hyperthermia through the disruption of tumor blood flow in HCC. Ultrasound treatment with hydralazine significantly reduced peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) of the CEUS time-intensity curves by 91.9 ± 0.9%, 95.7 ± 0.7%, and 96.6 ± 0.5%, compared to 71.4 ± 1.9%, 84.7 ± 1.1%, and 85.6 ± 0.7% respectively without hydralazine. Tumor temperature measurements showed that the cumulative thermal dose delivered by ultrasound treatment with hydralazine (170.8 ± 11.8 min) was significantly higher than that without hydralazine (137.7 ± 10.7 min). Histological assessment of the ultrasound-treated tumors showed that hydralazine injection formed larger hemorrhagic pools and increased tumor vessel dilation consistent with CEUS observations illustrating the augmentation of hyperthermic effects by hydralazine. In conclusion, we demonstrated that ultrasound hyperthermia can be enhanced significantly by hydralazine in murine HCC tumors by modulating tumor blood flow. Future studies demonstrating the safety of the combined use of ultrasound and hydralazine would enable the clinical translation of the proposed technique.
本研究通过最大限度地减少肿瘤血流介导的热量损失，探讨了使用肼屈嗪增强超声热疗治疗肝细胞癌（HCC）的效果。通过连续模式超声联合或不联合静脉注射肼屈嗪（5mg/kg）的方式，对小鼠 HCC 肿瘤进行了治疗。通过对比增强超声（CEUS）成像和组织学，分别评估了肿瘤血流和血管。肼屈嗪通过破坏 HCC 中的肿瘤血流，显著增强了超声热疗效果。与未用肼屈嗪组相比，用肼屈嗪治疗的超声组，CEUS 时间强度曲线的峰值增强（PE）、灌注指数（PI）和曲线下面积（AUC）分别降低了 91.9±0.9%、95.7±0.7%和 96.6±0.5%，而分别为 71.4±1.9%、84.7±1.1%和 85.6±0.7%。肿瘤温度测量结果表明，用肼屈嗪治疗的超声（170.8±11.8 分钟）所传递的累积热剂量明显高于未用肼屈嗪的（137.7±10.7 分钟）。对超声处理的肿瘤进行组织学评估显示，肼屈嗪注射形成了更大的出血池，并增加了肿瘤血管扩张，与 CEUS 观察结果一致，说明肼屈嗪增强了热疗效果。总之，我们证明了通过调节肿瘤血流，肼屈嗪可以显著增强超声热疗对小鼠 HCC 肿瘤的治疗效果。未来的研究如果能证明超声和肼屈嗪联合使用的安全性，将有望使该技术在临床上得到应用。
