Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Sci Rep. 2023 Mar 18;13(1):4487. doi: 10.1038/s41598-023-30286-8.
High intensity focused ultrasound (HIFU) systems have been approved for therapeutic ultrasound delivery to cause tissue ablation or induced hyperthermia. Microbubble agents have also been used in combination with sonication exposures. These require temperature feedback and monitoring to prevent unstable cavitation and prevent excess tissue heating. Previous work has utilized lower power and pressure to oscillate microbubbles and transfer energy to endothelial cells in the absence of thermally induced damage that can radiosensitize tumors. This work investigated whether reduced acoustic power and pressure on a commercial available MR-integrated HIFU system could result in enhanced radiation-induced tumor response after exposure to ultrasound-stimulated microbubbles (USMB) therapy. A commercially available MR-integrated HIFU system was used with a hyperthermia system calibration provided by the manufacturer. The ultrasound transducer was calibrated to reach a peak negative pressure of - 750 kPa. Thirty male New Zealand white rabbits bearing human derived PC3 tumors were grouped to receive no treatment, 14 min of USMB, 8 Gy of radiation in a separate irradiation cabinet, or combined treatments. In vivo temperature changes were collected using MR thermometry at the tumor center and far-field muscle region. Tissues specimens were collected 24 h post radiation therapy. Tumor cell death was measured and compared to untreated controls through hematoxylin and eosin staining and immunohistochemical analysis. The desired peak negative pressure of - 750 kPa used for previous USMB occurred at approximately an input power of 5 W. Temperature changes were limited to under 4 °C in ten of twelve rabbits monitored. The median temperature in the far-field muscle region of the leg was 2.50 °C for groups receiving USMB alone or in combination with radiation. Finally, statistically significant tumor cell death was demonstrated using immunohistochemical analysis in the combined therapy group compared to untreated controls. A commercial MR-guided therapy HIFU system was able to effectively treat PC3 tumors in a rabbit model using USMB therapy in combination with radiation exposures. Future work could find the use of reduced power and pressure levels in a commercial MR-guided therapy system to mechanically stimulate microbubbles and damage endothelial cells without requiring high thermal doses to elicit an antitumor response.
高强度聚焦超声（HIFU）系统已被批准用于治疗性超声输送以引起组织消融或诱导热疗。微泡剂也已与超声处理联合使用。这些需要温度反馈和监测，以防止不稳定的空化和防止过度的组织加热。以前的工作利用较低的功率和压力来振荡微泡，并将能量传递到血管内皮细胞，而不会产生热诱导的损伤，从而使肿瘤放射增敏。这项工作研究了在商业上可用的 MR 集成 HIFU 系统上降低声功率和压力是否可以导致暴露于超声刺激的微泡（USMB）治疗后增强辐射诱导的肿瘤反应。使用商业上可用的 MR 集成 HIFU 系统和制造商提供的高温系统校准。超声换能器经过校准，达到-750 kPa 的峰值负压。30 只雄性新西兰白兔携带人源 PC3 肿瘤，分为不治疗组、14 分钟 USMB 组、单独辐射柜 8 Gy 辐射组或联合治疗组。使用 MR 测温法在肿瘤中心和远场肌肉区域收集体内温度变化。在辐射治疗后 24 小时收集组织标本。通过苏木精和伊红染色和免疫组织化学分析测量肿瘤细胞死亡，并与未处理的对照进行比较。以前的 USMB 所需的期望峰值负压-750 kPa 出现在大约 5 W 的输入功率下。在监测的 12 只兔子中有 10 只，温度变化限制在 4°C 以下。腿部远场肌肉区域的中位数温度为接受 USMB 单独或与辐射联合治疗的组为 2.50°C。最后，在联合治疗组中，与未处理的对照组相比，通过免疫组织化学分析显示肿瘤细胞死亡具有统计学意义。商业 MR 引导治疗 HIFU 系统能够在兔模型中有效治疗 PC3 肿瘤，方法是使用 USMB 治疗联合辐射暴露。未来的工作可以在商业 MR 引导治疗系统中找到使用降低的功率和压力水平来机械刺激微泡并破坏血管内皮细胞，而无需高热剂量来引起抗肿瘤反应。
