Advances in low-frequency ultrasound combined with microbubbles in targeted tumor therapy

Wang, Liying; Zheng, Shusen

doi:10.1631/jzus.b1800508

Cited by 25 publications

(18 citation statements)

References 50 publications

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“…Several approaches aim to increase ultrasound's specificity. Molecularly targeted contrast agents, such as microbubbles [12,13] locally amplify ultrasound's disruptive effects, but are challenging to deploy in tumors due to the agents' poor extravasation [14]. An alternative approach involves low intensity pulsed ultrasound (LIPUS).…”

Section: Introductionmentioning

confidence: 99%

Selective ablation of cancer cells with low intensity pulsed ultrasound

Mittelstein

Schibber

et al. 2020

Applied Physics Letters

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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 No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Introductionmentioning

confidence: 99%

Selective ablation of cancer cells with low intensity pulsed ultrasound

Mittelstein

Schibber

et al. 2020

Applied Physics Letters

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“…Ultrasound-mediated microbubble (USMB) cavitation can create small pores on the cell membrane (sonoporation). [25][26][27] This temporary injury significantly increases the permeability of the cell membrane to large molecules. 28,29 The wound created by the USMB cavitation is self-healable, 30 and therefore such treatments do not permanently impair the normal functions of the treated cells.…”

Section: Introductionmentioning

confidence: 99%

Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane

Zhang

Chen

Fan

et al. 2020

Bioengineering & Transla Med

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The round window of the cochlea provides an ideal route for delivering medicines and gene therapy reagents that can cross the round window membrane (RWM) into the inner ear. Recombinant adeno-associated viruses (rAAVs) have several advantages and are recommended as viral vectors for gene transfection. However, rAAVs cannot cross an intact RWM. Consequently, ultrasound-mediated microbubble (USMB) cavitation is potentially useful, because it can sonoporate the cell membranes, and increase their permeability to large molecules. The use of USMB cavitation for drug delivery across the RWM has been tested in a few animal studies but has not been used in the context of AAV-mediated gene transfection. The currently available large size of the ultrasound probe appears to be a limiting factor in the application of this method to the RWM. In this study, we used home-made ultrasound probe with a decreased diameter to 1.5 mm, which enabled the easy positioning of the probe close to the RWM. In guinea pigs, we used this probe to determine that (1) USMB cavitation caused limited damage to the outer surface layer or the RWM, (2) an eGFP-gene carrying rAAV could effectively pass the USMB-treated RWM and reliably transfect cochlear cells, and (3) the hearing function of the cochlea remained unchanged. Our results suggest that USMB cavitation of the RWM is a good method for rAAV-mediated cochlear gene transfection with clear potential for clinical translation. We additionally discuss several advantages of the small probe size. K E Y W O R D S cochlea, cochlear gene therapy, gene delivery, Guinea pigs, recombinant adeno-associated virus, round window membrane, ultrasonic microbubbles cavitation Zhen Zhang and Zhengnong Chen contributed equally to this study.

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“…Due to the lack of cavitation nuclei in normal animals, we injected MBs into nude mice from the tail vein. This can not only significantly increase the number of cavitation nuclei enhancing the cavitation effect of low-frequency ultrasound but also greatly reduce the cavitation threshold [49].…”

Section: Ultrasound Instruments and Microbubbles (Mbs)mentioning

confidence: 99%

Cavitation-Enhanced Delivery of the Nanomaterial Graphene Oxide-Doxorubicin to Hepatic Tumors in Nude Mice Using 20 kHz Low-Frequency Ultrasound and Microbubbles

Shen

et al. 2020

Journal of Nanomaterials

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Graphene oxide (GO) is a kind of nanomaterial. Here, we explored its application in tumor treatment. We loaded doxorubicin onto the surface of GO to form graphene oxide-doxorubicin (GO-DOX). After injection of the contrast agent SonoVue microbubbles (MBs) into the tail vein of tumor-bearing nude mice, subcutaneous hepatic carcinomas inoculated with the HepG2 cell line were irradiated with 20 kHz low-frequency ultrasound (US). Subsequently, GO-DOX was injected into the tail vein of nude mice. Transmission electron microscopy (TEM) and TUNEL assays were performed to observe the curative effects. Biocompatibility tests of GO-DOX included routine blood cell counts, blood smears, serum biochemical assays, and histological sampling of important organs. It was found that the nanomaterial GO-DOX promoted apoptosis of tumor cells in nude mice. TEM of the USMB+GO-DOX treatment showed vascular endothelial cell wall rupture, widened endothelial cell gaps, black granules in the vascular lumen, interstitial erythrocyte leakage, and apparent apoptosis of tumor cells. There were no toxic side effects of GO-DOX on the blood system and in the major organs of these mice. Ultrasound cavitation destroys tumor blood vessels and enhances the release of nanomaterials to tumor cells of nude mice.

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Advances in low-frequency ultrasound combined with microbubbles in targeted tumor therapy

Cited by 25 publications

References 50 publications

Selective ablation of cancer cells with low intensity pulsed ultrasound

Selective ablation of cancer cells with low intensity pulsed ultrasound

Ultrasound‐microbubble cavitation facilitates adeno‐associated virus mediated cochlear gene transfection across the round‐window membrane

Cavitation-Enhanced Delivery of the Nanomaterial Graphene Oxide-Doxorubicin to Hepatic Tumors in Nude Mice Using 20 kHz Low-Frequency Ultrasound and Microbubbles

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