Ultrasonic Microbubbles Research Articles

Ultrasonic microbubbles promote mesenchymal stem cell homing to the fibrotic liver via upregulation of CXCR4 expression

ObjectiveTo investigate the mechanism of ultrasound microbubbles (UTMB) promoting stem cells homing to fibrotic liver.MethodsBone marrow derived mesenchymal stem cells (BMSCs) were divided into 5 groups with or without ultrasound microbubbles and continuously irradiated with ultrasound conditions of frequency 1 MHZ and output power 0.6 W/cm2 for different times, and then injected into a mouse model of liver fibrosis through the tail vein with or without ultrasound microbubbles, with sound intensity. The effect of ultrasound microbubbles on MSC expression of CXC chemokine receptor 4 (CXCR4) and homing fibrotic liver was evaluated by flow cytometry (FCM), western blot (WB) and immunohistochemistry (IHC) analysis.ResultsThe level of CXCR4 expression was significantly higher in the ultrasound microbubble group than in the non-intervention group (P < 0.05), and the number of MSC and the rate of CXCR4 receptor positivity in the ultrasound microbubble-treated liver tissues were significantly higher than in the non-intervention group (P < 0.01).ConclusionUltrasonic microbubbles can promote the expression of CXCR4 on the surface of MSCs, thus improving the homing rate of MSCs in fibrotic liver.

Use of UMFNPs/Ce6@MBs in multimodal imaging-guided sono-photodynamic combination therapy for hepatocellular carcinoma.

Early diagnosis of liver cancer and appropriate treatment options are critical for obtaining a good prognosis. However, due to technical limitations, it is difficult to make an early and accurate diagnosis of liver cancer, and the traditional imaging model is relatively simple. Therefore, we synthesized multifunctional diagnostic/therapeutic nanoparticles, UMFNPs/Ce6@MBs, loaded with ultra-small manganese ferrite nanoparticles (UMFNPs) and chlorin e6 (Ce6). This nanoplatform can take full advantage of hypoxia, acidic pH (acidosis) and increased levels of reactive oxygen species (e.g. H2O2) in the tumor microenvironment (TME). Specific imaging and drug release can also enhance tumor therapy by modulating the hypoxic state of the TME to achieve the combined effect of sonodynamic therapy and photodynamic therapy (SPDT). In addition, the prepared UMFNPs/Ce6@MBs have H2O2 and pH-sensitive biodegradability and can release UMFNPs and photosensitizer Ce6 in the TME while producing O2 and Mn2+. The obtained Mn2+ ion nanoparticles can be used for T1 magnetic resonance imaging of tumor-bearing mice, and the released Ce6 can provide fluorescence imaging function at the same time. Because UMFNPs/Ce6@MB ultrasonic microbubbles show good ultrasonic imaging results, UMFNPs/Ce6@MBs can simultaneously provide multi-modal imaging functions for magnetic resonance imaging (MRI), ultrasound and fluorescence imaging. In conclusion, UMFNPs/Ce6@MBs realize the synergistic treatment of SDT and PDT under multi-mode near-infrared fluorescence imaging and CEUS monitoring, demonstrating its great potential in tumor precision medicine.

Role of Ultrasonic Microbubbles in Treating Rheumatoid Arthritis: Enhancing the Efficacy of Tocilizumab via Contrast-Enhanced Ultrasound-Monitored, Ultrasound-Targeted Microbubble Destruction.

Our aim was to explore the feasibility of using ultrasound-targeted microbubble destruction (UTMD) to deliver tocilizumab and enhance its efficacy in treating rheumatoid arthritis (RA). Rats with adjuvant-induced arthritis were randomly assigned to one of five treatment groups: group 1, tocilizumab+microbubbles (MBs)+UTMD; group 2, tocilizumab+MBs; group 3, tocilizumab+saline; group 4, MBs+UTMD; group 5, no treatment. We employed a commercially available ultrasound (US) machine capable of performing contrast-enhanced ultrasound (CEUS) and UTMD simultaneously using a single probe. CEUS was performed to monitor the entry and collapse of MBs. After treatment, the rats' left hindlimb paws were harvested for immunohistochemical staining of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). After injection of the mixture of drugs and MBs with UTMD, significant enhancement was seen in the inflamed hindlimb paw regions, which subsided immediately on exposure to low-frequency US beams and re-appeared in the intervals between beam exposures. IL-6 expression was significantly lower in groups 1, 2 and 3 than in groups 4 and 5 (p < 0.01). Group 1 had the lowest level of IL-6 expression (p [G1 vs. G2] < 0.01, p [G1 vs. G3] < 0.01). The levels of TNF-α expression in groups 1, 2, and 3 were significantly lower than those in groups 4 and 5, but no difference was observed in these levels between groups 1-3. UTMD shows promise in enhancing the treatment efficacy of anti-IL-6 drugs for RA treatment.

Targeted delivery of isoliquiritigenin by ultrasonic microbubbles attenuate myocardial injury via suppressing inflammation and oxidative stress and activating AMPK/SIRT1/eNOS signaling pathway in rats

To investigate the protective efficacy of ultrasound targeted microbubble destruction (UTMD) combined with Isoliquiritigenin on myocardial injury in rats. The GK rat model of cardiomyopathy was successfully established by the induction of adriamycin. Then these rats with cardiomyopathy were randomly assigned into the model group, isoliquiritigenin microbubbles and ultrasound alone or combination group, using healthy ones as normal control. After 8-week consecutive treatment, the relevance indexes of diabetes, echocardiography as well as the hyperlipidemia, oxidative stress of model animals were examined. In addition, the fibrosis, morphological changes and inflammation response of myocardial tissues were also assessed. After further 4-week intervention, the blood biochemical indexes and the cardiac functions of model rats received the combined treatment were improved (all P < 0.05) compare to those received either monotherapy or saline. After chronic treatment, the heart/body weight ratio and serum cardiac index levels in model rats received combined treatment were significantly changed (all P < 0.05) compared with others. Furthermore, combination therapy could ameliorate excessive oxidation stress and inflammation response as well as up-regulate the expression levels of AMPK/SIRT1/eNOS signaling pathway. Targeted delivery of isoliquiritigenin by ultrasonic microbubbles can ameliorate the myocardial injury via activating AMPK/SIRT1/eNOS signaling pathways.

Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine.

The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.

Numerical simulation method of nonlinear contrast-enhanced ultrasound imaging

&lt;sec&gt;Contrast-enhanced ultrasound imaging (CEUS) based on the acoustic nonlinearity of ultrasonic microbubble has received great attention in recent years. Compared with conventional linear ultrasound imaging, nonlinear CEUS can further improve the imaging resolution while overcoming the challenge of clutter filtering. Simulation, acting as an effective tool for research on new mechanisms and technologies of ultrasound imaging, has been a long-term focus of computational acoustics. In the community of biomedical ultrasound, common sound field simulation tools are mainly based on finite element method (FEM), analytical method, &lt;i&gt;k&lt;/i&gt;-space pseudospectral method and finite-difference time-domain method (FDTD), which are relatively mature solutions for simulating the nonlinear characteristics of tissue. However, it is still not trivial to simulate nonlinear CEUS by using the prevailing methods, as the nonlinearity of microbubble is often not considered.&lt;/sec&gt;&lt;sec&gt;In this paper, we propose a simulation method of nonlinear CEUS imaging that successfully combines the microbubble nonlinearity and classic &lt;i&gt;k&lt;/i&gt;-space pseudospectral method. Specifically, forced oscillation response of the microbubble is computed based on the modified Rayleigh-Plesset equation and such a nonlinear response is further dealt as an additional source for analyzing the nonlinear component propagation and CEUS imaging. To investigate the performance of the proposed method, B-mode images of single microbubble and clustered microbubbles are simulated based on plane wave imaging. The plane wave based CEUS imaging can thus be carried out with different compounding angles and different contrast pulse sequencing (CPS) strategies (pulse inversion, amplitude modulation, pulse inversion &amp; amplitude modulation, and probe element alternation). Different soft-tissue and mechanical parameters of the microbubble can be adjusted by using the proposed nonlinear simulation strategy, thus providing efficient solution for CEUS simulation. Such a method can evaluate the performances of different CPS strategies, and further contribute to the CEUS development.&lt;/sec&gt;

Magnetic Nanodroplets for Enhanced Deep Penetration of Solid Tumors and Simultaneous Magnetothermal-Sensitized Immunotherapy against Tumor Proliferation and Metastasis.

The central cells of solid tumors are more proliferative and metastatic than the marginal cells. Therefore, more intelligent strategies for targeting cells with deep spatial distributions in solid tumors remain to be explored. In this work, a biocompatible nanotheranostic agent with a lipid membrane-coated, Fe3 O4 and perfluoropentane (PFP)-loaded, cRGD peptide (specifically targeting the integrin αvβ3 receptor)-grafted, magnetic nanodroplets (MNDs) is developed. The MNDs exhibit excellent magnetothermal conversion and controllable magnetic hyperthermia (MHT) through alternating magnetic field regulation. Furthermore, MHT-mediated magnetic droplet vaporization (MDV) induces the expansion of the MNDs to transform them into ultrasonic microbubbles, increasing the permeability of tissue and the cell membrane via the ultrasound-targeted microbubble destruction (UTMD) technique and thereby promoting the deep penetration of MNDs in solid tumors. More importantly, MHT not only causes apoptotic damage by downregulating the expression of the HSP70, cyclin D1, and Bcl-2 proteins in tumor cells but also improves the response rate to T-cell-related immunotherapy by upregulating PD-L1 expression in tumor cells, thus inhibiting the growth of both primary and metastatic tumors. Overall, this work introduces a distinct application of nanoultrasonic biomedicine in cancer therapy and provides an attractive immunotherapy strategy for preventing the proliferation and metastasis of deeply distributed cells in solid tumors.

Ultrasonic Microbubble Cavitation Enhanced Tissue Permeability and Drug Diffusion in Solid Tumor Therapy.

Chemotherapy has an essential role not only in advanced solid tumor therapy intervention but also in society’s health at large. Chemoresistance, however, seriously restricts the efficiency and sensitivity of chemotherapeutic agents, representing a significant threat to patients’ quality of life and life expectancy. How to reverse chemoresistance, improve efficacy sensitization response, and reduce adverse side effects need to be tackled urgently. Recently, studies on the effect of ultrasonic microbubble cavitation on enhanced tissue permeability and retention (EPR) have attracted the attention of researchers. Compared with the traditional targeted drug delivery regimen, the microbubble cavitation effect, which can be used to enhance the EPR effect, has the advantages of less trauma, low cost, and good sensitization effect, and has significant application prospects. This article reviews the research progress of ultrasound-mediated microbubble cavitation in the treatment of solid tumors and discusses its mechanism of action to provide new ideas for better treatment strategies.

Evaluation of Tumor Resection Effect of Color Doppler Ultrasound Positioning Guided Breast-Conserving Surgery Using Nano-Contrast Agent.

This study aimed to explore the clinical value of Fe3O4-based magnetic lipid nano-contrast agent in breast-conserving surgery for breast cancer using color doppler ultrasound positioning and to analyze the tumor resection effect of breast-conserving surgery. On account of Fe3O4 magnetic nanoparticles prepared by the chemical co-precipitation method, magnetic lipid ultrasonic microbubbles (MLU-MBs) were prepared by mechanical oscillation method after surface modification using polyethylene terephthalate (PET). Characterization and analysis of the prepared MLU-MBs were performed using scanning electron microscopy (SEM), energy spectrometer, transmission electron microscopy (TEM), and Fourier infrared spectroscopy (FIRS). A high-frequency alternating magnetic field was used to detect the heating of MLU-MBs and the color ultrasound machine was applied to observe the enhancement effect of the MLU-MBs on rabbit liver images. 92 patients undergoing breast-conserving surgery for breast cancer were taken as the research objects and were divided into a nano group (MLU-MB as contrast agent) and a control group (conventional contrast agent) according to the differences of intraoperative contrast agents, with 46 cases in each group. Before the surgery, both groups of patients were positioned and marked the tumor boundary under ultrasound. The differences in tumor volume (TV), amount of tissue removed, resection rate, and positive rate (PR) of resection margins were compared between the two groups. The results showed that the Fe3O4 magnetic nanoparticles were particles with an average particle size of about 15nm, and their iron and oxygen percentages were consistent with the content of Fe3O4. The MLU-MBs were spherical particles of about 1120nm, containing phosphorus (P), oxygen(O), and Ferrum (Fe). Under 30A and 220kHz of output current and frequency, the temperature rise of the MLU-MBs suspension with different concentrations was 10 ~ 60°C, and the temperature was constant after heating for 45 minutes. Compared with the rabbit liver parenchyma, the image was greatly enhanced. TV, the amount of tissue removed, the resection rate, and the PR of resection margins in the nano group were obviously lower than those in the control group (P<0.05). It showed that MLU-MBs with good image enhancement effect on account of Fe3O4 magnetic nanoparticles were successfully prepared and it could effectively reduce the PR of normal tissues and the positive margin of two-fold resection during breast-conserving surgery for breast cancer and showed good accuracy and stability.

Biostatistics of VHL-Gene Transfection in the Health Informatics Analysis of Renal Cell Carcinoma.

Objective In this paper, we study the role of the VHL gene in regulating the proliferation and apoptosis of renal cell carcinoma, as well as the safety and transfection efficiency of ultrasound microbubble gene transfection technology. Method We use kidney cancer cell lines as an in vitro research object and apply ultrasound microbubble gene transfection technology to transfect the VHL gene into kidney cancer cell line (786-0). The proliferation and apoptosis of cells were measured to clarify the inhibitory effect of the VHL gene in renal cell carcinoma. After that, pEGFP-VHL was transfected using ultrasonic microbubble and liposome gene transfection techniques, respectively, and the transfection efficiency was measured by immunofluorescence. Results Compared with untreated and 786-0 cells that are transfected with empty vector, the expression level of VHL gene mRNA in 786-0 cells that are transfected with pcDNA3.1-VHL was significantly increased, and the cell growth inhibition rate was significantly higher. The rate of apoptosis increased significantly. Transfection efficiency of the pEGFP-VHL gene after transfection of 786-0 cells for 48 h: control group 0, liposome group (35.55 ± 2.77) %, ultrasound microbubble group (18.27 ± 2.83) %, and two transfection methods on cells. There is no significant difference in the impact of vitality. Conclusion VHL gene expression can significantly inhibit the proliferation ability of renal cancer cell line 786-0 and promote its apoptosis. VHL gene is a potential target for gene therapy of kidney cancer.

Ultrasonic microbubble VEGF gene delivery improves angiogenesis of senescent endothelial progenitor cells

The therapeutic effects of ultrasonic microbubble transfection (UMT)-based vascular endothelial growth factor 165 (VEGF165) gene delivery on young and senescent endothelial progenitor cells (EPCs) were investigated. By UMT, plasmid DNA (pDNA) can be delivered into both young EPCs and senescent EPCs. In the UMT groups, higher pDNA-derived protein expression was found in senescent EPCs than in young EPCs. Consistent with this finding, a higher intracellular level of pDNA copy number was detected in senescent EPCs, with a peak at the 2-h time point post UMT. Ultrasonic microbubble delivery with or without VEGF improved the angiogenic properties, including the proliferation and/or migration activities, of senescent EPCs. Supernatants from young and senescent EPCs subjected to UMT-mediated VEGF transfection enhanced the proliferation and migration of human aortic endothelial cells (HAECs), and the supernatant of senescent EPCs enhanced proliferation more strongly than the supernatant from young EPCs. In the UMT groups, the stronger enhancing effect of the supernatant from senescent cells on HAEC proliferation was consistent with the higher intracellular VEGF pDNA copy number and level of protein production per cell in the supernatant from senescent cells in comparison to the supernatant from young EPCs. Given that limitations for cell therapies are the inadequate number of transplanted cells and/or insufficient cell angiogenesis, these findings provide a foundation for enhancing the therapeutic angiogenic effect of cell therapy with senescent EPCs in ischaemic cardiovascular diseases.

Preparation of Targeted Nano-Microbubble Contrast Agent and Its Application in the Diagnosis of Prostate Cancer

The objective of this study was to explore the application value of microbubble contrast materials in the diagnosis of prostate cancer. Firstly, ordinary nano-microbubbles and biotinylated nano-microbubbles were prepared by rotary evaporation method and mechanical vibration method. Then, the biotinylated anti-six-transmembrane prostate epithelial antigen-1 (STQWK-1) antibody was connected with the previously prepared nano-microbubbles with the help of biotin-avidin method, so as to generate a nano-microbubble contrast agent targeting prostate PC3 cells. While the contrast agent was characterized based on the immunofluorescence method, a microscope was applied to observe the in vitro targeting performance of targeted nano-microbubbles on PC3 cells. A prostate PC3 cell nude mouse transplanted tumor model was established, so that the contrast-enhanced ultrasound (CEUS) effect of different contrast agents on transplanted tumor was compared, which were applied in CEUS examination of prostate cancer patients. The results showed that the targeted nano-microbubbles could display circular green fluorescence under the microscope, and the blank nano-microbubbles had no display under the microscope. Both ultrasonic microbubbles were circular and evenly distributed. The in vitro targeting experiments indicated that targeted nano-bubbles could accumulate on the surface of prostate cancer PC3 cells, and tumor transplantation model proved that the targeted contrast agent carrying STQWK-1 antibody had a strong development and enhancement effect. In the diagnosis of prostate cancer patients, the sensitivity (83.3% vs. 52%), specificity (66.7% vs. 36.3%), accuracy (75% vs. 47.2%), and other indicators of the diagnosis of targeted nano-bubbles prepared showed marked advantages compared with routine trans-rectal US (TRUS) diagnosis. The contrast agent prepared in this study could be specifically targeted to prostate PC3 cells in vitro, which had the effect of development and enhancement and had a good diagnostic performance in the diagnosis of prostate cancer.

A Study on Application of Ultrasonic Wave and Ozone Micro-Bubbles in Leafy Vegetables Washing

The demand for vegetable consumption is essential issue to serve citizens. Excessive protective chemical elimination which is applied advanced solutions brings high effects being investigated by domestic and international scientists. In this report, research team conducted and designed the vegetable washing machine integrated with the ultrasonic power and Ozone microbubbles to wash out plentiful protective chemicals attaching to surfaces of leafy vegetables. Followingly, using Taguchi method for four kinds of vegetables including salad, water spinach, Chinese cabbage, and mustard greens verifies the effectiveness of solutions. Vegetable samples are treated soaking pool making ultrasonic wave and Ozone microbubbles raging from 1.0ppm to 2.0ppm. The practical results demonstrated that the method using the ultrasonic power and Ozone microbubbles has high effects on eradicating protective chemical on leafy vegetables.

Optimization of Orifice Shape and Oscillatory Displacement of an Ultrasonic Microbubble Generator to Increase Microbubble Yield

Optimization of Orifice Shape and Oscillatory Displacement of an Ultrasonic Microbubble Generator to Increase Microbubble Yield

MiR‑378 in combination with ultrasonic irradiation and SonoVue microbubbles transfection inhibits hepatoma cell growth.

Ultrasonic microbubbles in combination with microRNA (miRNAs/miRs) exhibited promising effects on cancer treatments. The aim was to investigate the role of miR-378 in hepatoma cells and the efficiency of it in combination with ultrasonic irradiation and SonoVue® microbubbles method for cell transfection. HuH-7, Hep3B and SK-Hep1 cells were transfected with an miR-378 mimic using only Lipofectamine® 3000 or combined with SonoVue microbubbles and ultrasonic irradiation at 0.5 W/cm2 for 30 sec. mRNAs and protein levels of Cyclin D1, Bcl-2, Bax, Akt, p53 and Survivin were detected by reverse transcription-quantitative PCR and western blotting, respectively. Cell survival rate, proliferation, cell cycle and apoptosis were determined by Cell Counting Kit-8, cell double cytochemical staining and flow cytometry, respectively. It was found that using a combination of ultrasonic irradiation and the SonoVue microbubbles method increased the effectiveness of miR-378 transfection into hepatocellular carcinoma (HCC) cells, and increased the inhibition of cell survival and proliferation. Moreover, miR-378 increased the rate of apoptosis and upregulated the expression of Bax and p53, and suppressed the cell cycle and downregulated the expression of Cyclin D1, Bcl-2, Akt, β-catenin and Survivin much more effectively in the HCC cell line by applying the combined method. Thus, miR-378 was shown to be a suppressive factor to reduce proliferation and increase apoptosis in HCC cells. Additionally, the combination of ultrasonic irradiation and SonoVue microbubbles method was more efficient in the transfection of miRNA.

Post-processing radio-frequency signal based on deep learning method for ultrasonic microbubble imaging

BackgroundImproving imaging quality is a fundamental problem in ultrasound contrast agent imaging (UCAI) research. Plane wave imaging (PWI) has been deemed as a potential method for UCAI due to its’ high frame rate and low mechanical index. High frame rate can improve the temporal resolution of UCAI. Meanwhile, low mechanical index is essential to UCAI since microbubbles can be easily broken under high mechanical index conditions. However, the clinical practice of ultrasound contrast agent plane wave imaging (UCPWI) is still limited by poor imaging quality for lack of transmit focus. The purpose of this study was to propose and validate a new post-processing method that combined with deep learning to improve the imaging quality of UCPWI. The proposed method consists of three stages: (1) first, a deep learning approach based on U-net was trained to differentiate the microbubble and tissue radio frequency (RF) signals; (2) then, to eliminate the remaining tissue RF signals, the bubble approximated wavelet transform (BAWT) combined with maximum eigenvalue threshold was employed. BAWT can enhance the UCA area brightness, and eigenvalue threshold can be set to eliminate the interference areas due to the large difference of maximum eigenvalue between UCA and tissue areas; (3) finally, the accurate microbubble imaging were obtained through eigenspace-based minimum variance (ESBMV).ResultsThe proposed method was validated by both phantom and in vivo rabbit experiment results. Compared with UCPWI based on delay and sum (DAS), the imaging contrast-to-tissue ratio (CTR) and contrast-to-noise ratio (CNR) was improved by 21.3 dB and 10.4 dB in the phantom experiment, and the corresponding improvements were 22.3 dB and 42.8 dB in the rabbit experiment.ConclusionsOur method illustrates superior imaging performance and high reproducibility, and thus is promising in improving the contrast image quality and the clinical value of UCPWI.

Blood Brain Barrier Disruption by Focused Ultrasound and Microbubbles: A Numerical Study on Mechanical Effects

Introduction: Microbubbles are widely used as contrast agent in diagnostic ultrasound. Recently they have shown good potential for applications in the therapeutic field such as drug delivery to the brain. Recent studies have shown focused ultrasound in conjunction with injected micro-bubbles could temporarily disrupt blood-brain barrier and let therapeutic agents transport into the brain tissue. The main aim of current study was to investigate, the interactions between ultrasonic acoustic field and microbubbles and the resultant mechanical effects on microvessels. Materials and Methods: In this study, we have used numerical approach to simulate microbubble confined in a microvessel filled with viscose fluid as blood. In the main stream of our study two crucial equations have been solved: equation of bubble oscillation on the bubble surface in an ultrasonic acoustic field (R-P equation), and equations of mass conservation and continuity (Navier Stokes) in fluid domain. Microbubble radius change, subjected to ultrasonic wave, and the force-fluid coupling which cause high velocity gradient and subsequent exertion of shear stress on interior vessel wall have been calculated. In this study microvessel considered as a viscoelastic solid. Acoustic pressure amplitude has been varied between 1.5P0 and 5P0 (P0 is hydrostatic pressure in fluid, P0~ 104.6kPa) with a constant frequency (f=1MHz). Then at a constant pressure of 2.5P0 acoustic frequency has been changed between 1 and 6MHz. Shear stress and transmural pressure, two important metrics for mechanical effects and vessel damage, have been calculated for each case. Results: The results obtained from the preliminary analysis of simulation study demonstrate that by increasing acoustic pressure both shear stress and transmural pressure increase linearly between 4-20 and 300-650kPa respectively. When the acoustic pressure reached the value 5P0 vessel ruptured and at this point, our simulation was stopped. This study has shown that by increasing acoustic frequency, relative difference of bubble radius, increase to%66 and then decrease to %12. In this case, shear stress and transmural pressure reached almost to a maximum of 10 and 450kPa respectively. Conclusion: The present study has gone some way towards enhancing our understanding of interaction between the acoustic field and micro bubbles. Mechanical effects on vessel wall are pressure and frequency dependant and it’s important to find a threshold for acoustic pressure that below it vessel damages won’t occur. This study has identified threshold for acoustic pressure is about 0.45P0. Also, it is very important to consider microbubbles resonance frequency at which maximum amplitude of oscillation and mechanical effects occur.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Anti-tumor effect of ultrasound-induced Nordy-loaded microbubbles destruction

Background: Synthesized dl-Nordihydroguaiaretic acid (dl-NGDA or “Nordy”) can inhibit the growth of malignant human tumors, especially the tumor angiogenesis. However, its liposoluble nature limits its in vivo efficacy in the hydrosoluble circulation of human.Purpose: We tried to use the ultrasonic microbubble as the carrier and the ultrasound-induced destruction for the targeted release of Nordy and evaluate its in vitro and in vivo anti-tumor effect.Methods: Nordy-loaded lipid microbubbles were prepared by mechanical vibration. Effects of ultrasound-induced Nordy-loaded microbubbles destruction on proliferation of human umbilical vein endothelial cells (HUVECs), tumor derived endothelial cells (Td-ECs), and rabbit transplanted VX2 tumor models were evaluated.Results: The ultrasound-induced Nordy-loaded microbubbles destruction inhibited the proliferations of HUVECs and Td-ECs in vitro, and inhibited the tumor growth and the microvasculature in vivo. Its efficacy was higher than those of Nordy used only and Nordy with ultrasound exposure.Conclusion: Ultrasonic microbubbles can be used as the carrier of Nordy and achieve its targeted release with improved anti-tumor efficacy in the condition of ultrasound-induced microbubbles destruction.

Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.

BackgroundThere is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors.MethodsPhospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model.ResultsThe average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle.ConclusionsThe Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.