Abstract
Focused ultrasound (FUS) has proven its efficacy in non-invasive, radiation-free cancer treatment. However, the commonly used low-frequency high-intensity focused ultrasound (HIFU) destroys both cancerous and healthy tissues non-specifically through extreme heat and inertial cavitation with low spatial resolution. To address this issue, we evaluate the therapeutic effects of pulsed (60 Hz pulse repetition frequency, 1.45 ms pulse width) high-frequency (20.7 MHz) medium-intensity (spatial-peak pulse-average intensity ISPPA < 279.1 W/cm2, spatial-peak temporal-average intensity ISPTA < 24.3 W/cm2) focused ultrasound (pHFMIFU) for selective cancer treatment without thermal damage and with low risk of inertial cavitation (mechanical index < 0.66), in an in vivo subcutaneous B16F10 melanoma tumor growth model in mice. The pHFMIFU with 104 μm focal diameter is generated by a microfabricated self-focusing acoustic transducer (SFAT) with a Fresnel acoustic lens. A three-axis positioning system has been developed for automatic scanning of the transducer to cover a larger treatment volume, while a water-cooling system is custom-built for dissipating non-acoustic heat from the transducer surface. Initial testing revealed that pHFMIFU treatment can be applied to a living animal while maintaining skin temperature under 35.6 °C without damaging normal skin and tissue. After eleven days of treatment with pHFMIFU, the treated tumors were significantly smaller with large areas of necrosis and apoptosis in the treatment field compared to untreated controls. Potential mechanisms of this selective, non-thermal killing effect, as well as possible causes of and solutions to the variation in treatment results, have been analyzed and proposed. The pHFMIFU could potentially be used as a new therapeutic modality for safer cancer treatment especially in critical body regions, due to its cancer-specific effects and high spatial resolution.
Highlights
Focused ultrasound (FUS) is a powerful and effective tool for non-invasive therapy
Using pulsed highfrequency (18 MHz) low-intensity (ISPPA < 15.14 W/cm2) focused ultrasound generated by microfabricated selffocusing acoustic transducers (SFAT), we demonstrated selective cytolysis on both monolayers [27] and threedimensional (3D) spheroids [28] of cancer cells with high spatial resolution of 100 and 160 μm, respectively
We found that the acoustic intensity thresholds (AIT) for cytolysis of cancerous cells are substantially lower than those for benign cells, likely due to less organized actin cytoskeletal pattern compared to benign cells [27]
Summary
Focused ultrasound (FUS) is a powerful and effective tool for non-invasive therapy. With the energy of ultrasound focused onto a small volume of tissue that can be deep inside the body, the treatment efficacy and precision is greatly enhanced with less side effects compared to less focused radiation [1]. High-intensity focused ultrasound (HIFU) has demonstrated good therapeutic effects in the treatment of tumors [2] in the prostate [1, 3], pancreas [4], breast [5], and brain [6] In most of these applications, low-frequency (< 4 MHz) focused ultrasound of high intensity (with spatial-peak pulse-average intensity ISPPA usually ranging from 1,000 to 10,000 W/cm2) induces rapid heating in tissue [7], raising its temperature above 60 °C, to cause irreversible cell damage (coagulative necrosis) [8]. To further confirm the effectiveness of this non-thermal selective cancer treatment with high-frequency focused ultrasound, we have developed an SFAT along with a treatment system for in vivo treatment of B16F10 subcutaneous melanoma tumors in mice
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