Low Frequency Nanobubbles-Enhanced Ultrasound Mechanotherapy for Noninvasive Cancer Surgery

A unique theranostic ultrasound-based technology for low-energy mechanical ablation of tissues.

Noninvasive ultrasound surgery can be achieved using focused ultrasound to locally affect the targeted site without damaging intervening tissues. Mechanical ablation and histotripsy use short and intense acoustic pulses to destroy the tissue via a purely mechanical effect. Here we show that coupled with low-frequency excitation, targeted microbubbles and/or nanobubbles could serve as mechanical therapeutic warheads that trigger potent mechanical effects at specific locations inside the body under the direction of focused ultrasound. Upon low-frequency excitation (below 300 kHz), high-amplitude microbubble oscillations occur at substantially lower pressures as compared to higher MHz ultrasonic frequencies. Here, we used these enhanced oscillations to achieve tumor cells and tissue fractionation at low pressures of hundreds of kilopascals (an order of magnitude less than the pressures used in standard mechanical ablation). We demonstrate these capabilities using two low frequencies of 250 kHz and 80 kHz in vitro, in cell cultures, and in tumor-bearing mice models.

Advantageous therapeutic platforms for the treatment of cancer, which utilize advantageous bubbles (MB) and/or nanobubbles (NB) that can be administered to a subject in need thereof, combined with the application of low-frequency ultrasound (US), to facilitate remote low energy US surgery of tumors, by triggering the MB or NB oscillations in target tissues, leading to mechanical effects on these tissues.

The technology is suitable for treating various types of cancers and tumors, such as solid tumors including breast, lung, prostate, colon, pancreatic, liver, bone metastases, melanoma, bladder, kidney, sarcomas, carcinomas, oral and oropharyngeal cancers, thyroid cancers, uterine cancers, neuroblastoma, and lymphomas. 

Application PCT/IL2022/050609

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