Selective ablation of cancer cells with low intensity pulsed ultrasound

Abstract

Ultrasound can be focused into deep tissues with millimeter precision to perform non-invasive ablative therapy for diseases such as cancer. In most cases, this ablation uses high intensity ultrasound to deposit non-selective thermal or mechanical energy at the ultrasound focus, damaging both healthy bystander tissue and cancer cells. Here we describe an alternative low intensity pulsed ultrasound approach that leverages the distinct mechanical properties of neoplastic cells to achieve inherent cancer selectivity. We show that when applied at a specific frequency and pulse duration, focused ultrasound selectively disrupts a panel of breast, colon, and leukemia cancer cell models in suspension without significantly damaging healthy immune or red blood cells. Mechanistic experiments reveal that the formation of acoustic standing waves and the emergence of cell-seeded cavitation lead to cytoskeletal disruption, expression of apoptotic markers, and cell death. The inherent selectivity of this low intensity pulsed ultrasound approach offers a potentially safer and thus more broadly applicable alternative to non-selective high intensity ultrasound ablation.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cell stiffness predicts cancer cell sensitivity to ultrasound as a selective superficial cancer therapy

“…1d). Based on previous reports showing differences in stiffness between metastatic MDA-MB-231 and MCF-7 breast cancer cells and non-tumorigenic MCF-10A cells 5,20 , we speculate that F-actin, together with cell mechanics and behavior, explain selective cancer cell death following ultrasound treatment.…”

“…6) correlated with treatment duration and repetition rate, suggesting that ultrasound has the potential to effectively treat superficial tumors. Since ultrasound is known to cause cell death 20,22,23,57 via non-thermal mechanical effects [58][59][60] , using low-frequency ultrasound (20 kHz) is advantageous because it provides cavitation and acoustic streaming as a result of naturally dissolved gas bubble oscillation 61 without the need for external intervention, such as cavitation nuclei or microbubbles. All these natural phenomena, which increase as the ultrasound energy level increases, can trigger biophysical effects, such as microstreaming, micro-jetting, and free radical formation, which may affect cell viability 62 .…”

“…The use of ultrasound as a tool in cancer therapy has been studied since the 1940s 15,16 Studies from our laboratory 17 and by others [18][19][20][21] have found that certain malignant cells are highly sensitive to ultrasonic irradiation. Ultrasound produces a variety of non-thermal mechanical bio-effects 22,23 , inducing shear stress 24,25 in cells and stretch/compression distributions in the vicinity of the cellular surface through microstreaming around bubbles, cavitation, and acoustic streaming 22 .…”

Focused Ultrasound Stimulates ER Localized Mechanosensitive PANNEXIN-1 to Mediate Intracellular Calcium Release in Invasive Cancer Cells

“…FUS produces a focused beam of acoustic energy that precisely and accurately reaches large targets in the body without damaging surrounding normal cells (Mittelstein et al, 2020). One of the most striking findings of our study is the suggestion that FUS may also directly stimulate intracellular mechanosensory proteins located on particular membrane limited organelles such as ER.…”

A dynamical model of oncotripsy by mechanical cell fatigue: selective cancer cell ablation by low-intensity pulsed ultrasound

“…Following these leads, Mittelstein et al [16] have endeavoured to assess the oncotripsy effect in carefully designed laboratory tests involving a number of cancerous cell lines in aqueous suspension. They have developed a system for testing oncoptripsy that includes a tunable source of ultrasonic transduction in signal communication with a system that allows control of several parameters, including frequency and pulse duration.…”