Mild hyperthermia with magnetic resonance-guided high-intensity focused ultrasound for applications in drug delivery.

PURPOSE: Mild hyperthermia (40-45 °C) is a proven adjuvant for radiotherapy and chemotherapy. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) can non-invasively heat solid tumours under image guidance. Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (>40 °C) and may improve drug delivery to solid tumours when combined with mild hyperthermia. The objective of this study was to develop and implement a clinically relevant MR-HIFU mild hyperthermia heating algorithm for combination with LTSLs. MATERIALS AND METHODS: Sonications were performed with a clinical MR-HIFU platform in a phantom and rabbits bearing VX2 tumours (target = 4-16 mm). A binary control algorithm was used for real-time mild hyperthermia feedback control (target = 40-41 °C). Drug delivery with LTSLs was measured with HPLC. Data were compared to simulation results and analysed for spatial targeting accuracy (offset), temperature accuracy (mean), homogeneity of heating (standard deviation (SD), T10 and T90), and thermal dose (CEM43). RESULTS: Sonications in a phantom resulted in better temperature control than in vivo. Sonications in VX2 tumours resulted in mean temperatures between 40.4 °C and 41.3 °C with a SD of 1.0-1.5 °C (T10 = 41.7-43.7 °C, T90 = 39.0-39.6 °C), in agreement with simulations. 3D spatial offset was 0.1-3.2 mm in vitro and 0.6-4.8 mm in vivo. Combination of MR-HIFU hyperthermia and LTSLs demonstrated heterogeneous delivery to a partially heated VX2 tumour, as expected. CONCLUSIONS: An MR-HIFU mild hyperthermia heating algorithm was developed, resulting in accurate and homogeneous heating within the targeted region in vitro and in vivo, which is suitable for applications in drug delivery.

Improved volumetric MR-HIFU ablation by robust binary feedback control.

Volumetric high-intensity focused ultrasound (HIFU) guided by multiplane magnetic resonance (MR) thermometry has been shown to be a safe and efficient method to thermally ablate large tissue volumes. However, the induced temperature rise and thermal lesions show significant variability, depending on exposure parameters, such as power and timing, as well as unknown tissue parameters. In this study, a simple and robust feedback-control method that relies on rapid MR thermometry to control the HIFU exposure during heating is introduced. The binary feedback algorithm adjusts the durations of the concentric ablation circles within the target volume to reach an optimal temperature. The efficacy of the binary feedback control was evaluated by performing 90 ablations in vivo and comparing the results with simulations. Feedback control of the sonications improved the reproducibility of the induced lesion size. The standard deviation of the diameter was reduced by factors of 1.9, 7.2, 5.0, and 3.4 for 4-, 8-, 12-, and 16-mm lesions, respectively. Energy efficiency was also improved, as the binary feedback method required less energy to create the desired lesion. These results show that binary feedback improves the quality of volumetric ablation by consistently producing thermal lesions of expected size while reducing the required energy as well.

Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry.

A volumetric sonication method is proposed that produces volume ablations by steering the focal point along a predetermined trajectory consisting of multiple concentric outward-moving circles. This method was tested in vivo on pig thigh muscle (32 ablations in nine animals). Trajectory diameters were 4, 12, and 16 mm with sonication duration depending on the trajectory size and ranging from 20 to 73 s. Despite the larger trajectories requiring more energy to reach necrosis within the desired volume, the ablated volume per unit applied energy increased with trajectory size, indicating improved treatment efficiency for larger trajectories. The higher amounts of energy required for the larger trajectories also increased the risk of off-focus heating, especially along the beam axis in the near field. To avoid related adverse effects, rapid volumetric multiplane MR thermometry was introduced for simultaneous monitoring of the temperature and thermal dose evolution along the beam axis and in the near field, as well as in the target region with a total coverage of six slices acquired every 3 s. An excellent correlation was observed between the thermal dose and both the nonperfused (R=0.929 for the diameter and R=0.964 for the length) and oedematous (R=0.913 for the diameter and R=0.939 for the length) volumes as seen in contrast-enhanced T1-weighted difference images and T2-weighted postsonication images, respectively. Histology confirmed the presence of a homogeneous necrosis inside the heated volumes. These results show that volumetric high-intensity focused ultrasound (HIFU) sonication allows for efficiently creating large thermal lesions while reducing treatment duration and also that the rapid multiplane MR thermometry improves the safety of the therapeutic procedure by monitoring temperature evolution both inside as well as outside the targeted volume.