MR-guided ultrasound-stimulated microbubble therapy enhances radiation-induced tumor response

Abstract

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.

Radiation combined with ultrasound and microbubbles: A potential novel strategy for cancer treatment

“…Positive TUNEL staining corroborated the cell destruction response areas on respective H&E stains. Combined treatments (17.9% ± 5.7%) showed greater areas of cell death which were more diffuse across the tumor compared to XRT- only (7.6% ± 3.8%) or USMB-only (5.7% ± 2.5%) treatments indicating a radiation enhancement effect using USMB therapy in large tumor models [83] .…”

“…Recent work has scaled up this methodology to be applicable for treatment systems that can be used in clinical settings alongside ultrasound-imaging guidance, and independently with MRI-guidance, for large animal tumor models and first-in-human cancer patient treatments [80] , [83] , [84] .…”

“…In an additional study using MRI-guided FUS (MRgFUS), New Zealand White rabbits were used to host PC-3 xenografts on the hind legs [83] . USMB treatment consisted of a bolus injection of microbubbles (Definity), followed by sonication for 14 min using an MRgFUS system (Sonalleve, Profound Medical).…”

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