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Objectives: To assess the efficacy and safety of sulfur hexafluoride microbubbles on ultrasound-guided high-intensity focused ultrasound (HIFU) ablation of uterine fibroids., Methods: Studies that compared HIFU-microbubble combination with HIFU-only in patients with uterine fibroids were searched from inception to April 2022. The standardized mean difference (SMD) or relative risk (RR) with 95% confidence interval (CI) for different outcome parameters was calculated., Results: Seven studies were included, with a total of 901 patients (519 in the combination group and 382 in the HIFU-only group). The energy consumption for treating 1 cm 3 of the lesion in the combination group was less than that in the HIFU-only group [SMD =  - 2.19, 95%CI (- 3.81, - 0.57), p = 0.008]. The use of microbubbles was associated with shortening the duration of the treatment and sonication [SMD =  - 2.60, 95%CI (- 4.09, - 1.10), p = 0.0007; SMD =  - 2.11, 95%CI (- 3.30, - 0.92), p = 0.0005]. The rates of significant greyscale changes during HIFU were greater in the combination group, as well as the increase of non-perfused volume ratio [RR = 1.26, 95%CI (1.04, 1.54), p = 0.02; SMD = 0.32, 95%CI (0.03, 0.61), p = 0.03]. The average sonication durations to reach significant greyscale changes and for ablating 1 cm 3 of the fibroid lesion were shorter in the combination group [SMD =  - 1.24, 95%CI (- 2.02, - 0.45), p = 0.002; SMD =  - 0.22, 95%CI (- 0.42, - 0.02), p = 0.03]. The two groups had similar post-HIFU adverse effects, while the combination group had fewer intraprocedural adverse events like abdominal pain, sacrum pain, and leg pain., Conclusions: Sulfur hexafluoride microbubbles can be safely used to enhance and accelerate the ablation effects of HIFU in the treatment of uterine fibroids., Clinical Relevance Statement: The combination of HIFU with sulfur hexafluoride microbubbles offers a promising non-invasive treatment option for patients with uterine fibroids., Key Points: • Sulfur hexafluoride microbubbles combined with ultrasound-guided high-intensity focused ultrasound (USgHIFU) has potential advantages in the treatment of uterine fibroids. • Sulfur hexafluoride microbubbles not only enhance the effects of USgHIFU treatment for uterine fibroids but also shorten its duration. • Sulfur hexafluoride microbubbles do not increase the incidence of USgHIFU-related adverse events in the treatment of uterine fibroids., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The aim of this study was to identify the potential and mechanisms of microbubble-mediated cavitation in promoting apoptosis and suppressing invasion in cancer cells. AsPC-1 cells were used and divided into four groups: control group, microbubble-only (MB) group, ultrasound-only (US) group and ultrasound plus microbubble (US + MB) group. Pulse ultrasound was used at a frequency of 360 kHz and a SPPA (spatial peak, pulse average) intensity of 1.4 W/cm 2 for 1 min (duty rate = 50%). Then cells in the four groups were cultured for 24 h. Cell Counting Kit‑8 (Biosharp, Hefei, Anhui, China) revealed decreased cell viability in the US + MB group. Western blot confirmed that there were increased cleaved caspase‑3 and Bcl-2-associated X protein levels and decreased B‑cell lymphoma‑2 (Bcl-2) levels, as well as increased intracellular calcium ions and downregulated cleaved caspase-8, in the US + MB group. With respect to proliferation, cells in the US + MB group had lower expression of Ki67 and the weakened colony formation ability. The transwell invasion assay revealed that invasion ability could be decreased in AsPC-1 cells in the US + MB group. Further, it was found that cells in the US + MB group had lower levels of hypoxia-inducible factor-1α (HIF-1α) and vimentin and higher levels of E-cadherin compared with the other three groups. Finally, the US + MB cells had less invadopodium formation. In conclusion, these results suggest that microbubble-mediated cavitation promotes apoptosis and suppresses invasion in AsPC-1 cells., Competing Interests: Conflict of interest disclosure The authors declare there are no competing financial interests in relation to this research., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Cancer stem cells (CSCs) are responsible for cancer therapeutic resistance and metastasis. To date, in addition to surgery, chemotherapy, and radiotherapy, gene delivery has emerged as a potential therapeutic modality for ovarian cancer. Efficient and safe targeted gene delivery is complicated due to the tumor heterogeneity barrier. Ultrasound (US)-stimulated microbubbles (MBs) have demonstrated a method of enabling non-invasive targeted gene delivery., Purpose: The purpose of our study was to show the utility of poly(ethylene glycol)-SS-polyethylenimine-loaded microbubbles (PSP@MB) as an ultrasound theranostic and redox-responsive agent in a gene delivery system., Patients and Methods: PSP nanoparticles were conjugated to the MB surface through biotin-avidin linkage, increasing the gene-loading efficiency of MB. The significant increase in the release of genes from the PSP@MB complexes was achieved upon ultrasound exposure. The positive surface charge in PSP@MB can condense the plasmid through electrostatic interactions; agarose-gel electrophoresis further confirmed the ability of PSP@MB to condense plasmids. The morphology, particle sizes and zeta potential of PSP@MB were characterized by transmission electron microscopy and dynamic light scattering., Results: Laser confocal microscopy showed that the combination of ultrasound with PSP@MB could promote the cellular uptake of plasmids. Plasmids which encode enhanced green fluorescence protein (EGFP) reporter genes or luciferase reporter genes were delivered to CSCs in vitro and to subcutaneous xenografts in vivo via the combination of ultrasound with PSP@MB. Gene transfection efficiency was evaluated by fluorescence microscopy and In Vivo Imaging Systems. This study demonstrated that the combination of ultrasound with PSP@MB can remarkably promote gene delivery to solid tumors as well as diminishing the toxicity towards normal tissues in vivo. The combination of PSP@MB and the use of ultrasound can efficiently enhance accumulation, extravasation and penetration into solid tumors., Conclusion: Taken together, our study showed that this novel PSP@MB and ultrasound-mediated gene delivery system could efficiently target CSCs., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Liufu et al.)

High intensity focused ultrasound (HIFU) has been regarded as a promising technology for treating cancer and other severe diseases noninvasively. In the present study, dual modality magnetic ultrasound contrast agent microbubbles (MBs) were synthesized by loading the super paramagnetic iron oxide nanoparticles (SPIOs) into the albumin-shelled MBs (referred as SPIO-albumin MBs). Then, both experimental measurements and numerical simulations were performed to evaluate the ability of SPIO-albumin MBs of enhancing HIFU-induced thermal effect. The results indicated that, comparing with regular albumin-shelled MBs, the SPIO-albumin MBs would lead to quicker temperature elevation rate and higher peak temperature. This phenomenon could be explained by the changes in MBs' physical and thermal properties induced by the integration of SPIOs into MB shell materials. In addition, more experimental results demonstrated that the enhancement effect on HIFU-induced temperature elevation could be further strengthened with more SPIOs combined with albumin-shell MBs. These observations suggested that more violent cavitation behaviors might be activated by ultrasound exposures with the presence of SPIOs, which in turn amplified ultrasound-stimulated thermal effect. Based on the present studies, it is reasonable to expect that, with the help of properly designed dual-modality magnetic MBs, the efficiency of HIFU-induced thermal effect could be further improved to achieve better therapeutic outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sonoporation has been widely accepted as a significant tool for gene delivery as well as some bio-effects like hemolysis, bringing in high demands of looking into its underlying mechanism. A two-dimensional (2D) boundary element method (BEM) model was developed to investigate microbubble-cell interaction, especially the morphological and mechanical characteristics around the close-to-bubble point (CP) on cell membrane. Based on time evolution analysis of sonoporation, detailed information was extracted from the model for analysis, including volume expansion ratio of the bubble, areal expansion ratio of the cell, jet velocity and CP displacement. Parametric studies were carried out, revealing the influence of different ultrasound parameters (i.e., driving frequency and acoustic pressure) and geometrical configurations (i.e., bubble-cell distance and initial bubble radius). This model could become a powerful tool not only for understanding bubble-cell interactions, but also for optimizing the strategy of sonoporation, such that it could be safer and of higher efficiency for biological and medical studies especially in clinics., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Multi-parameter fitting algorithms, which are currently used for the characterization of coated-bubbles, inevitably introduce uncertainty into the results. Therefore, a better technique that can accurately determine the microbubbles' mechanical properties is urgently needed. A comprehensive technology combining atomic force microscopy, optical, and acoustic measurements with simulations of coated-bubble dynamics was developed. Using this technique, the mechanical parameters (size distribution, shell thickness, elasticity, and viscosity) of hybrid (ultrasound/magnetic-resonance-imaging) contrast microbubbles and their structure-property relationship were determined. The measurements indicate that when more superparamagnetic iron oxide nanoparticles are embedded in the microbubbles' shells, their mean diameter and effective viscosity increase, and their elastic modulus decreases. This reduces the microbubbles' resonance frequency and thus enhances acoustic scattering and attenuation effects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Ultrasonic cavitation is a novel potential approach for cancer treatment. We optimized the techniques of ultrasonic cavitation to enhance antitumor efficacy in a mouse model with human pancreatic cancer. A polydisperse MB contrast agent formulation (TS-P) with a mean number diameter of 1.9 μm was depleted in small diameter particles by differential centrifugation, producing an "up-sized" size distribution (TS-PL) possessing a mean diameter of 2.9 μm. Mice bearing the XPA-1-RFP pancreatic tumor were treated daily for 3 consecutive days with either up-sized or standard MB. Both treatment cohorts exhibited a significant reduction in tumor volume relative to the untreated control cohort (P < 0.05), and TS-PL group has significantly reduction in tumor volume (1215.1± 324.7 mm3) compared with standard TS-P group (2131.2±753.4 mm3) (P < 0.05). The treatment with TS-PL resulted in more tumor cell necrosis and apoptosis than with TS-P. Decreased expression of CD31 and MVD was observed histologically in tumors treated with TS-PL relative to TS-P. This study demonstrates that tuning the size distribution of existing contrast agent products, specifically to reduce the concentration of small MB, is required for enhanced anti-tumor cavitation activity.

The goal of this study was to determine whether ultrasound mediated microbubbles destruction (UMMD) could inhibit colon cancer growth in a mouse model. Six-week-old balb/c female nude mice were subcutaneously inoculated with HT29-GFP cells (HT29 cells labeled with green fluorescent dye) in axilla to establish a xenograft mouse model of colon carcinoma, which were randomly divided into five groups (n=10 each): group A (blank group): no treatment; group B (saline only); group C (saline+ultrasound exposure); group D (intravenous microbubbles only); and group E (intravenous microbubbles+ultrasound exposure). Treatment of each group was performed on days 20, 21, and 22 after inoculation. Tumor growth and metastatic spread were monitored by the whole-body fluorescent imaging, tumor volume growth and body weight growth curve were obtained as well. The mice were euthanized 30 days after treatment. Specimens of the tumor tissues were evaluated pathologically using light microscopy and transmission electron microscopy. Necrosis percentages, microvascular density and tumor cells damage of each tumor were assessed histologically. Our data indicate that: (1) tumor growth in group E (intravenous microbubbles+ultrasound exposure) was significantly decreased after four weeks post inoculation, compared with other control treatments (P<0.05); (2) the tumor weight at sacrifice in group E was significantly lower than that in other groups; (3) The intravenous microbubbles combined with ultrasound exposure treated mice showed significantly decreased expression levels of CD31. (4)The pathological changes of absence of nucleus membrane, chromatin condensation, mitochondrial vacuolation and hemorrhagic damage of microvessel were observed in the tumors of group E only, whereas these changes occurred rarely in other groups; and (5) no metastatic lesion was found in any group throughout this study using whole-body fluorescent imaging, and the skin of the mouse in group E was intact after UMMD treatment. Our results suggest that UMMD can be used as a promising novel therapeutic strategy to treat colon cancer., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Ultrasound super-resolution imaging through localisation and tracking of microbubbles can achieve sub-wave-diffraction resolution in mapping both micro-vascular structure and flow dynamics in deep tissue in vivo. Currently, it is still challenging to achieve high accuracy in localisation and tracking particularly with limited imaging frame rates and in the presence of high bubble concentrations. This study introduces microbubble image features into a Kalman tracking framework, and makes the framework compatible with sparsity-based deconvolution to address these key challenges. The performance of the method is evaluated on both simulations using individual bubble signals segmented from in vivo data and experiments on a mouse brain and a human lymph node. The simulation results show that the deconvolution not only significantly improves the accuracy of isolating overlapping bubbles, but also preserves some image features of the bubbles. The combination of such features with Kalman motion model can achieve a significant improvement in tracking precision at a low frame rate over that using the distance measure, while the improvement is not significant at the highest frame rate. The in vivo results show that the proposed framework generates SR images that are significantly different from the current methods with visual improvement, and is more robust to high bubble concentrations and low frame rates. [ABSTRACT FROM AUTHOR]

Abstract: This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB+sham cavitation). Group 3 received naked microbubbles and ultrasonic cavitation (MB+cavitation). Group 4 received Endostar loaded microbubbles and ultrasonic cavitation (Endostar-MB+cavitation). Ultrasonic cavitation was performed using a high-power custom built sonicator. Contrast-enhanced ultrasound imaging (CEUS) was used to measure tumor blood flow before and after ultrasonic cavitation. In vivo fluorescence imaging was performed to monitor changes in tumor volume. Immunohistochemistry was performed to assess CD31, VEGFR-2 and alpha-v beta-3 integrin expression within the tumor. Apoptosis of the tumor cells was determined by TUNEL assay, and ultrastructural changes within the tumor were examined by electron microcopy. Ultrasonic cavitation with Endostar-MB demonstrated a significantly greater inhibition of tumor blood flow on day 7 and tumor growth on day 16 compared with naked MB and control groups. The Endostar-MB treated mice showed significantly decreased expression VEGFR-2 and alpha-v beta-3 integrin, and increased apoptosis of tumor cells and degradation of the tumor ultrastructure. Our findings indicated that the anti-vascular and anti-tumor effects of ultrasonic cavitation could be potentiated by simultaneously delivering an anti-angiogenic drug in colon cancer. [Copyright &y& Elsevier]

Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. [ABSTRACT FROM AUTHOR]

• The application of ultrasound and microbubbles (US + MBs) enhances the extravasation of macromolecular substance through blood–brain barrier via transcytosis mechanism. • The mechanical interaction between oscillating microbubbles and cell membranes results in direct membrane deformation and generates both mechanical and sonochemical effects. • The formation of pits on the cellular membrane surface is a critical step in the initiation of endocytosis or transcytosis processes. • US + MBs application induced membrane hyperpolarization and increase of cytosolic calcium concentration. • Mechanical interaction between oscillating microbubbles and cell membrane plays a necessary role in the dynamin-/caveolae-/clathrin- related transcytosis. The blood–brain barrier (BBB) maintains brain homeostasis, regulates influx and efflux transport, and provides protection to the brain tissue. Ultrasound (US) and microbubble (MB)-mediated blood–brain barrier opening is an effective and safe technique for drug delivery in-vitro and in-vivo. However, the exact mechanism underlying this technique is still not fully elucidated. The aim of the study is to explore the contribution of transcytosis in the BBB transient opening using an in-vitro model of BBB. Utilizing a diverse set of techniques, including Ca2+ imaging, electron microscopy, and electrophysiological recordings, our results showed that the combined use of US and MBs triggers membrane deformation within the endothelial cell membrane, a phenomenon primarily observed in the US + MBs group. This deformation facilitates the vesicles transportation of 500 kDa fluorescent Dextran via dynamin-/caveolae-/clathrin- mediated transcytosis pathway. Simultaneously, we observed increase of cytosolic Ca2+ concentration, which is related with increased permeability of the 500 kDa fluorescent Dextran in-vitro. This was found to be associated with the Ca2+-protein kinase C (PKC) signaling pathway. The insights provided by the acoustically-mediated interaction between the microbubbles and the cells delineate potential mechanisms for macromolecular substance permeability. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as a promising therapeutic approach for cancer treatment. This therapy focuses on the specificity and memory of the immune system against malignant cells to achieve a sustained cure with minimal toxicity. However, the effectiveness of immunotherapy is often limited by the insufficient delivery and low accumulation of therapeutic molecules in tumors. Ultrasound exposures with the presence of microbubbles can be used as an effective method to greatly increase cell membrane permeability and enhance tissue accessibility to drugs or genes, thereby improving the access of therapeutic molecules into non-permeable tissues and enhancing the therapeutic outcomes. In this review, we discuss challenges in current tumor immunotherapy and feasible approaches that could potentially overcome these obstacles with the help of ultrasound; thereafter, we elaborate on the recent advantages of ultrasound-mediated delivery approach in tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine whether ultrasound (US) mediated microbubbles (MBs) destruction (UMMD) could inhibit VX2 orthotopic hepatic tumor growth in rabbit models. Twenty-four VX2 orthotopic hepatic tumor rabbit models were randomly divided into four groups (n  =  6 each): saline group, SonoVue alone group, US alone group, US + SonoVue group. Tumor volume (TV), peak intensity (PI) of contrast enhanced ultrasound (CEUS) in US + SonoVue group were significantly lower than that in other groups after treatment ( P   <  0.05, for all). Immunohistochemical analysis of tumor tissue showed that microvascular density (MVD) in US + SonoVue group was significantly lower than that in other groups ( P   <  0.05, for all). Extensive interstitial hemorrhage, intravascular thrombosis, destroyed nucleus membrane, mitochondria vacuolation and chromatin condensation were observed in US + SonoVue group, whereas these changes were rarely appeared in other groups. Our study indicated that UMMD could inhibit the growth of VX2 hepatic tumors in rabbits by irreversible destroying tumor microvessel and tumor cells. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the accuracy of multi-detector computed tomography (MDCT) with double contrast-enhanced ultrasound (DCEUS), in which intravenous microbubbles are used alongside oral contrast-enhanced ultrasound, in determining the gross classification of patients with gastric carcinoma (GC). Altogether, 239 patients with GC proved by histology after endoscopic biopsy were included in this study. DCEUS and MDCT were performed pre-operatively. The diagnostic accuracies of DCEUS and MDCT in determining the gross classification were calculated and compared. The overall accuracy of DCEUS in determining the gross appearance of GC was higher than that of MDCT (84.9% vs. 79.9%, p < 0.001). There was no significant difference in accuracy between DCEUS and MDCT for Borrmann I and IV classifications of advanced gastric cancer (χ(2), p = 0.323 for Borrmann type I, p = 0.141 for Borrmann type IV). The accuracy of DCEUS for early GC and Borrmann II and III classifications of GC was higher than that of MDCT (χ(2), p = 0.000 for all). DCEUS may be regarded as a valuable complementary tool to MDCT in determining the gross appearance of gastric adenocarcinoma pre-operatively. [ABSTRACT FROM AUTHOR]