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BACKGROUND:Immunotherapy enhances the anti-cancer immune response in many ways,so combined immunotherapy is a better choice.Ultrasound-targeted microbubble destruction technique delivers drugs,genes,antibodies and cytokines directly to the cytoplasm of immune cells and enhances the immune response.However,the application of ultrasound-targeted microbubble destruction technique in the treatment of ovarian cancer with both CXC chemokine receptor 4 antibody and programmed death-ligand 1 antibody has not been reported. OBJECTIVE:To investigate the effect of ultrasound irradiation on the proliferation and migration of ovarian cancer cells with CXC chemokine receptor 4 antibody and programmed death-ligand 1 antibody double targeted nanobubbles. METHODS:IOSE-80 normal ovarian epithelial cells,SKOV3 and CAOV3 ovarian cancer cells were cultured and expanded.Double labeling fluorescence immunoassay was used to co-locate CXC chemokine receptor 4 and programmed death-ligand 1 protein.Western blot assay was used to detect the relative expression of CXC chemokine receptor 4 and programmed death-ligand 1 protein in three kinds of cells and screen out the experimental cells,i.e.,pure nanobubbles,nanobubbles carrying CXC chemokine receptor 4 antibody,nanobubbles carrying CXC chemokine receptor 4 and programmed death-ligand 1 antibody.SKOV3 ovarian cancer cells in the logarithmic growth phase were taken and divided into six groups for treatment.Group A was added with McCoy's 5A medium.Group B was added with McCoy's 5A medium containing stromal cell-derived factor-1.Group C was added with pure nanobubble solution and McCoy's 5A medium containing stromal cell-derived factor-1.Group D was added with nanobubble solution containing CXC chemokine receptor 4 antibody and McCoy's 5A medium containing stromal cell-derived factor-1.Group E was added with nanobubble solution containing CXC chemokine receptor 4 and programmed death-ligand 1 antibody and McCoy's 5A medium containing stromal cell-derived factor-1.Pure nanobubble solution was added in group F.After ultrasonic irradiation for 120 seconds and incubation for 48 hours,the survival rate of cells was measured by CCK-8 assay,and the healing and migration ability of cells in groups B-E were measured by wound healing test. RESULTS AND CONCLUSION:(1)Immunofluorescence staining showed that CXC chemokine receptor 4 and programmed death-ligand 1 protein could be expressed in all three kinds of cells.Western blot assay showed that the expression levels of CXC chemokine receptor 4 and programmed death-ligand 1 in SKOV3 and CAOV3 ovarian cancer cells were significantly higher than those in IOSE-80 normal ovarian epithelial cells(P<0.05).(2)CCK-8 assay results exhibited that the cell survival rate of group B was higher than that of group A(P<0.05).The cell survival rate of group F was lower than that of group A(P<0.05).The cell survival rate of groups B-E decreased gradually,and there were significant differences between the two groups(P<0.05).(3)Wound healing test demonstrated that the cell healing rate of groups B-E decreased gradually,and there were significant differences between the two groups(P<0.05).(4)The results show that the use of CXC chemokine receptor 4 antibody and programmed death-ligand 1 antibody double targeted nanobubbles under ultrasound-targeted microbubble destruction can significantly inhibit the proliferation and migration of ovarian cancer cells.
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BACKGROUND:Gold nanoparticles are of great significance in the development of multifunctional transdermal drug delivery systems.Smaller gold nanoparticles can penetrate the dermis through the intercellular pathway,but are limited to their easy agglomeration and colloidal morphology,which makes it difficult to exert effects on low delivery efficiency. OBJECTIVE:To develop an ultrasound-optimized hydrogel delivery system by combining phase change nanodroplets with bio-adhesive hydrogel for percutaneous delivery of gold nanoparticles. METHODS:The ultrasound-responsive nanodroplets loaded with gold nanoparticles were prepared by the emulsion solvent evaporation method and loaded into the polydopamine-modified methylacryloyl gelatin hydrogel to prepare a composite hydrogel scaffold.The structure and chemical composition of the ultrasound-responsive nanogold carrier were characterized.The microstructure,porosity,permeability,rheology,in vitro hemostasis,and antibacterial properties of the composite hydrogel were characterized.The cell compatibility of the hydrogel scaffold was evaluated by live/dead staining,and the optimization effects of low-intensity pulsed ultrasound on the permeability,porosity,and mechanical properties of hydrogel were evaluated. RESULTS AND CONCLUSION:(1)Transmission electron microscopy and ultraviolet-visible spectroscopy proved the successful construction of nanogold carriers.The particle size and potential results demonstrated that the synthesized nanoscaled ultrasonic responsive carrier had good stability.(2)Live/dead cell staining proved that the prepared composite hydrogel scaffold had certain biocompatibility.(3)Scanning electron microscopy exhibited that the prepared composite hydrogel scaffold had a porous network structure,and numerous pores of about 2 μm appeared inside the macropores after the addition of nanodroplets and ultrasonic irradiation.The permeability experiment displayed that low-intensity pulsed ultrasound could optimize the porosity and permeability of hydrogel materials.The hemostatic performance of the composite hydrogel scaffold was better than that of the hemostatic sponge and polydopamine@methylacrylylated gelatin hydrogel scaffold.Under the irradiation of low-intensity pulsed ultrasound,the composite hydrogel scaffolds had good antioxidant effects and antibacterial properties.(4)Thermal imaging results manifested that gold nanoparticles were encapsulated in ultrasound-responsive nanobubbles,and more uniform dispersion could be obtained under ultrasonic excitation.(5)The results of the mechanical property test demonstrated that the storage modulus of the hydrogel increased before and after loading gold nanoparticles-nanodroplets,which showed stronger mechanical properties.The elongation at break was 122%,and the ductility was better than that without gold nanoparticles-nanodroplets(P<0.05).(6)These findings indicate that the composite hydrogel scaffold has good biocompatibility,antibacterial property,oxidation resistance,and hemostatic effect.
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In the past few decades, microbubbles were widely used as ultrasound contrast agents in the field of tumor imaging. With the development of research, ultrasound targeted microbubble destruction technology combined with drug-loaded microbubbles can achieve precise drug release and play a therapeutic role. As a micron-scale carrier, microbubbles are difficult to penetrate the endothelial cell space of tumors, and nano-scale drug delivery system—nanobubbles came into being. The structure of the two is similar, but the difference in size highlights the unique advantages of nanobubbles in drug delivery. Based on the classification principle of shell materials, this review summarized micro/nanobubbles used for ultrasound diagnosis or treatment and discussed the possible development directions, providing references for the subsequent development.
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Early diagnosis of acute rejection is of significance for the protection of renal allograft function. Pathological puncture biopsy is the gold standard for the diagnosis of acute rejection of renal allografts. Nevertheless, it may provoke multiple complications, such as bleeding, infection and renal parenchymal injury, which limit its widespread application. In recent years, the sensitivity of contrast-enhanced ultrasound in the diagnosis of acute rejection has been constantly improved. Ultrasound-targeted microbubble technique has further enhanced the diagnostic specificity of contrast-enhanced ultrasound, making it possible to replace pathological puncture biopsy. Besides, in the field of acute rejection treatment, microbubble ultrasonic cavitation may promote local delivery of immunosuppressants by inducing sonoporation and exhibit anti-rejection effect. In this article, the application of contrast-enhanced ultrasound in the diagnosis and treatment of acute rejection after kidney transplantation was reviewed, aiming to provide reference for widespread application of contrast-enhanced ultrasound in kidney transplantation.
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Objective:To investigate the mechanism of miR-1290 mediated by ultrasound microbubbles on the proliferation, apoptosis and invasion of ovarian cancer cells by regulating the expression of DKK3.Methods:Logarithmic SKOV3 cells were divided into Control group, miR-1290 NC group, microbubble treatment (MB) group, miR-1290 inhibitor group and miR-1290 inhibitor-MB group. The targeting relationship between miR-1290 and DKK3 was verified by double luciferase assay; RT-PCR was used to detect the expression of miR-1290 and DKK3 mRNA in SKOV3 cells; the activity of SKOV3 cells was detected by MTT assay; the apoptosis of SKOV3 cells was detected by flow cytometry; cell scratch test and Transwell test were used to detect the migration and invasion abilities of SKOV3 cells; Western blot was used to detect the expression of protein.Results:The double luciferase experiment showed that miR-1290 had a targeting relationship with DKK3, and miR-1290 could negatively target DKK3; Compared with miR-1290 NC group [24, 48, 72 h: (0.53 ± 0.05), (0.82 ± 0.06), (1.24 ± 0.06) ], MB group [24, 48, 72 h: (0.43 ± 0.06), (0.71 ± 0.03), (1.03 ± 0.03) ], miR-1290 inhibitor group [24, 48, 72 h: (0.41 ± 0.03), (0.66 ± 0.04), (0.78 ± 0.05) ], miR-1290 inhibitor MB group [24, 48, 72 h: (0.33 ± 0.04), (0.54 ± 0.05), (0.67 ± 0.06) ] SKOV3 cell proliferation activity decreased significantly ( P<0.05), compared with the migration rate and invasion number of SKOV3 cells in miR-1290 NC group [ (45.98 ± 4.11) %, (235.14 ± 5.78) ], the migration rate and invasion number of SKOV3 cells in MB group [ (36.77 ± 4.24) %, (189.57 ± 4.58) ], miR-1290 inhibitor group [ (32.14 ± 3.78) %, (165.35 ± 5.01) ], and miR-1290 inhibitor MB group [ (20.40 ± 3.01) %, (86.21 ± 4.23) ] decreased significantly,the expression of DKK3 mRNA and protein, apoptosis rate, apoptosis promoting protein C-Caspase-3 and Bax in SKOV3 cells increased greatly ( P<0.05) ; the above indexes of SKOV3 cells in miR-1209 NC group and Control group had no great difference ( P>0.05) . Conclusion:MiR-1290 can negatively regulate the expression of DKK3, while ultrasound microbubble can down regulate the expression of miR-1290 and up regulate the expression of DKK3, thereby inhibiting the proliferation, migration and invasion of ovarian cancer SKOV3 cells and promoting the apoptosis of cancer cells.
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Nowadays,the application of ultrasound is not only used in clinical imaging,but also extended in the study of drug delivery.Diagnostic ultrasound combined with microbubbles can effectively open the biological barriers,which can enhance the targeted delivery of drugs and be beneficial to the combination of ultrasound and disease treatment.This review summarizes the biological effects of ultrasound,the characteristics of ultrasound microbubbles and the potential ability that solving the biological barrier problems in cancer therapy by using ultrasound targeted microbubble destruction,hoping to provide some reference for the further development of therapeutic ultrasound as a safe and effective drug targeted delivery strategy.
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Objective:To investigate the tumor perfusion enhancement induced by low intensity ultrasound stimulated microbubble cavitation (USMC) combined with programmed cell death-Ligand 1(PD-L1) antibody on improving the immune microenvironment of solid tumors.Methods:Tumor-bearing mice were divided into 4 groups: Control ( n=26) group, USMC ( n=27) group, anti-PD-L1 ( n=27) group and USMC+ anti-PD-L1 ( n=27) group. USMC treatment was performed with a VINNO 70 ultrasound theranostics system. Tumor perfusion was evaluated by contrast-enhanced ultrasound (CEUS). The anti-tumor efficacy was assessed by the tumor growth curve and the survival time of mice. The number and function of CD8 + T cells, the differentiation of CD4 + T cells, the proportion of MDSC and the phenotype distribution of TAM in tumors were analyzed by flow cytometry. The content of CXCL9, CXCL10 and HIF-1α in tumor were detected by ELISA. The expression of VEGF in tumor tissues was analyzed by immunofluorescence. Results:CEUS showed that the values of PI and AUC of tumors were significantly increased after USMC compared with before USMC (all P<0.05). USMC combined with anti-PD-L1 therapy did suppress the tumor progression. FCM showed the number, the expression of proliferation antigen Ki67, the secretion of IFN-γ and Granzyme B of CD8 + T cells in tumors were higher in combined group than those in other three groups after therapy (all P<0.05). Meantime, the proportion of Th1 was rose while Tregs and MDSC were declined and the polarization of TAM was toward M1 type by combined therapy. ELISA analysis showed that the combined therapy also increased the concentration of CXCL9, CXCL10 and decreased the content of HIF-1α in tumors (all P<0.05). Meanwhile, the immunofluorescence expression of VEGF was significantly lower in combined group than that in the control group after treatment ( P<0.05). Conclusions:Tumor perfusion enhancement by USMC combined with PD-L1 antibody therapy could improve tumor immune microenvironment and USMC might be a novel effective method for potentiating PD-L1 antibody immunotherapy.
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Objective:To evaluate the ability of vascular endothelial growth factor receptor 2(VEGFR2)/integrin α vβ 3 dual-targeted microubble (MBD) to target angiogenesis of renal cell carcinoma (RCC) in vivo. Methods:Non-targeted microbubble (MBN) USphere LA was employed as a template to prepare single- and dual-targeted microbubbles which could bind VEGFR2 and/or integrin α vβ 3 (MBV and MBI) by the biotin-avidin bridging method. A total of 40 RCC nude mice models were established by subcutaneously injecting 786-O cells.Twenty of the models were all injected with MBN, MBV, MBI and MBD in a random order, and the other 20 models were registered for antibody blocking assays. The results of ultrasound images were used for quantitative analyses, and the following quantitative parameters were obtained: intensity increment (a 1), peak halving speed (a 2), curve rising slope (a 3), perfusion time (t 0), time to peak (TTP), peak intensity (PI), mean transit time (MTT) and area under the curve (AUC) for the first three minutes, peak intensity at 10 s before (P 1) and after (P 2) ultrasound destruction, and the differences of tissue enhancement (dTE) between P 1 and P 2 (dTE=P 1-P 2). All the quantitative parameters of four contrast agents and the antibody blocking assays were compared.Besides, the immunohistochemical assays were performed to evaluate the expression of CD31, VEGFR2 and integrin α vβ 3 in tumor tissues. Results:The differences of parameters of a 1, a 3, t 0, TTP, PI and P 2 among four different microbubbles had no statistical significances (all P>0.05), and all parameters between the two single-targeted contrast agents were not statistically different (all P>0.05). The parameters of AUC, MTT, P 1 and dTE all showed a trend that dual-targeted bubbles > single-targeted bubbles > non-targeted bubbles (all P<0.05). On the contrary, the trend of dual-targeted bubbles < single-targeted bubbles < non-targeted bubbles (all P<0.05) was observed for a 2. In the antibody blocking experiment, a 2 was faster after the antibody injection ( P<0.001), while AUC, MTT, P 1 and dTE were all lower than those before the antibody injection ( P<0.001), and the other parameters were not statistically different before and after the antibody injection (all P>0.05). Immunohistochemical analyses confirmed the high expression of CD31, VEGFR2 and integrin β 3 in tumor tissues. Conclusions:The VEGFR2 and integrin α vβ 3 dual-targeted microbubble has a good potential to target the angiogenesis of human RCC in vivo.
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Objective:To investigate the effect of vancomycin (Vm)-loaded microbubbles (MBs) combined with ultrasound targeted microbubble destruction (UTMD) technique on the morphological structure, thickness and bacterial viability of methicillin-resistant Staphylococcus aureus (MRSA) biofilms.Methods:Vm-MBs were prepared by thin film hydration. Sterile coverslips in a diameter of 13 mm were placed in 24-well plates to construct in vitro biofilm models using MRSA as the test strain, and the biofilm morphology was observed by naked eye and light microscopy after crystal violet staining. LIVE/DEAD, SYTO59 and DIL were used to stain biofilms and MBs, respectively. After staining, the biofilm morphology and position of the biofilm in relation to MBs were observed using laser confocal scanning microscopy. The biofilms were divided into control group, Vm group, Vm-MBs group, UTMD group and Vm-MBs+UTMD group according to the random number table method, with 9 samples in each group. After biofilms of each group were treated accordingly for 24 hours, the morphological and structural changes of biofilms in each group were observed using laser confocal scanning microscopy and scanning electron microscopy following LIVE/DEAD staining; the difference in biofilm density in each group was measured with the aid of an enzyme marker following crystal violet staining; the difference in biofilm thickness and bacterial viability in each group were observed by laser confocal scanning microscopy. Results:The prepared Vm-MBs met the experimental requirements. The constructed biofilm model observed by naked eye, light microscopy and laser confocal scanning microscopy showed that the biofilm structure was dense with a relatively uniform thickness of (13.8±0.2)nm, a small amount of dead bacteria inside the membrane and the percentage of live bacteria of (94.9±0.3)%. Laser confocal scanning microscopy showed that MBs could penetrate into deeper layers of biofilms. After the respective treatment was given to each group for 24 hours, Laser confocal scanning microscopy and scanning electron microscopy following LIVE/DEAD staining showed that the biofilm morphological structure was most significantly disrupted in Vm-MBs+UTMD group compared to control, Vm, Vm-MBs and UTMD groups. In Vm-MBs+UTMD group, a large number of dead bacteria was observed, with only a few scattered planktonic bacteria and irregular changes in cell membrane morphology. Crystal violet staining showed that the biofilm density was significantly lower in Vm-MBs+UTMD group compared to control group ( P<0.05), while the differences between Vm, Vm-MBs and UTMD groups were not statistically significant (all P>0.05). Laser confocal microscopy showed that the biofilm thickness was thinner in Vm-MBs, UTMD and Vm-MBs+UTMD groups compared to control group (all P<0.05), with no significant difference between Vm group and control group ( P>0.05) and that the biofilm thickness was thinner in Vm-MBs+UTMD group compared to Vm, Vm-MBs and UTMD groups (all P<0.01), with no significant differences between the other groups (all P>0.05). Bacterial activity in Vm, Vm-MBs, UTMD and Vm-MBs+UTMD groups was significantly lower than that in control group (all P<0.01), with lower in Vm-MBs+UTMD group compared to Vm, Vm-MBs and UTMD groups (all P<0.01), but without significant difference between the other groups (all P>0.05). Conclusion:Vm-MBs combined with UTMD technology can effectively destroy the biofilm morphological structure to reduce biofilm thickness. Meanwhile, Vm-MBs combined with UTMD technology can release antibiotics and significantly decrease bacterial viability to improve antibiotic bactericidal efficacy.
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Objective:To investigate the effect of ultrasound combined with 4-hydroxyphenyl-retinamide (4-HPR) lipid microbubbles on type Ⅰ collagen α1 chain (COL1A1) protein expression in keloid-derived fibroblasts.Methods:In vitro cultured keloid-derived fibroblasts were divided into 3 groups: control group receiving conventional culture with incomplete Dulbecco′s modified Eagle′s medium (DMEM) , 4-HPR lipid microbubble group cultured with incomplete DMEM containing 15 mg/L 4-HPR lipid microbubbles, and ultrasound + 4-HPR lipid microbubble group cultured with incomplete DMEM containing 15 mg/L 4-HPR lipid microbubbles under ultrasound treatment. After 24-hour treatment, reverse transcription (RT) -PCR and Western blot analysis were performed to determine the mRNA and protein expression of COL1A1 in keloid-derived fibroblasts in each group. Intergroup comparison was carried out by using t test. Results:The mRNA relative expression level of COL1A1 was 1.00 ± 0.18, 0.69 ± 0.15 and 0.35 ± 0.18 in the control group, 4-HPR lipid microbubble group and ultrasound + 4-HPR lipid microbubble group respectively, and the protein relative expression level of COL1A1 was 0.93 ± 0.03, 0.74 ± 0.07 and 0.44 ± 0.06 in the above 3 groups respectively. Moreover, the mRNA and protein expression of COL1A1 was significantly lower in the 4-HPR lipid microbubble group and ultrasound + 4-HPR lipid microbubble group than in the control group ( P < 0.05 or 0.001) , and lower in the ultrasound + 4-HPR lipid microbubble group than in the 4-HPR lipid microbubble group ( P < 0.05) . Conclusion:Ultrasound combined with 4-HPR lipid microbubbles could markedly inhibit the mRNA and protein expression of COL1A1 in keloid-derived fibroblasts.
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Ultrasound therapy and considerable progress in molecular imaging technologies have allowed the use of ultrasonic microbubbles not only in image enhancement but also in targeted drug or gene delivery as drug or gene carriers, respectively. Hence, ultrasound microbubbles carrying drugs or genes have become a novel type of tumor-targeting therapy technology. They do not emit radiation and are thus safe. Additionally, they are efficient and easy to reuse and facilitate drug or gene release. All these features offer attractive prospects for the treatment of liver cancer and provide novel treatment ideas for the disease. This article reviews the mechanism, applications, and existing problems of ultrasonic microbubbles in the treatment of liver cancer.
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Objective:To investigate the effects of ultrasound microbubble-mediated RasGAP SH3-binding protein 1 (G3BP1) transfection on the proliferation and migration of human liver cancer HepG2 cells.Methods:HepG2 cells were treated with ultrasound targeted microbubble destruction (UTMD) technology-mediated si-G3BP1. The expression of G3BP1 in HepG2 cell lines was detected by Western blot, and the silencing efficiency was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. HepG2 cell proliferation and migration were analyzed by flow cytometry, methyl thiazolyl tetrazolium (MTT) , EdU staining, colony formation experiment, wound healing experiment, Transwell experiment and Western blot.Results:After silencing G3BP1 in HepG2 cells, its mRNA and protein levels were significantly reduced (1.01±0.03 vs 0.27±0.03, 1.02±0.01 vs 0.33±0.04) ; UTMD-mediated si-G3BP1 could significantly reduce the proliferation rate (31.49±3.09 vs 12.51±1.02) , proliferation activity (1.20±0.13 vs 0.46±0.31) , EdU-positive cell rate (99.23±1.01 vs 36.75±4.03) , colony formation rate (96.45±1.21 vs 32.67±2.62) , scratch healing rate (97.58±1.04 vs 42.33±2.56) , migration rate (94.28±2.33 vs 39.36±2.51) and Ki67, Cyclin D1, Vimentin protein levels, increase E-cadherin protein levels.Conclusion:UTMD-mediated si-G3BP1 can inhibit the proliferation and migration of human liver cancer HepG2 cells.
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Introduction: We examined the thermophysiological effects of ultrafine bubble (UB) bathing in comparison with microbubble (MB) and freshwater (FW) bathing. Subjects and Methods: Seven healthy women aged 35.6±2.9 years provided informed consent to participate in the study. After a 10-min rest, each subject engaged in UB, MB, and FW bathing (on separate days) at 40°C for 10 min. During the experiment, tympanic temperature, local sweat rate, local skin temperature, heat flow, and heart rate variability were continuously recorded. Subjective assessments of thermal sensation and comfort were rated on a visual analog scale between 0 to 100. Results: Increases in tympanic temperature and mean body temperature were highest during MB bathing, and similar increases were observed during UB and FW bathing. Local sweating was highest during MB bathing and lowest during UB bathing. A significant interaction was observed between local sweating during bathing and bathing style (P<0.001). The increase in local sweat rate relative to body temperature was lowest during UB bathing and highest during MB bathing. Discussion: During UB bathing, UBs and MBs that were generated in high concentrations in the bathtub decreased the flow of heat to the body, thereby suppressing an increase in tympanic temperature and yielding the lowest local sweat late. However, during MB bathing, in which a moderate concentration of UBs and MBs were generated, the increase in heat flow due to the convection of hot water exceeded the decrease in heat flow due to the bubbles. Conclusions: The results suggest that bubble properties and convection characteristics altered the balance of heat flow, leading to differences in the thermoregulatory response during and after bathing.
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Ultrasound contrast agent microbubbles combined with low frequency ultrasound named as low-frequency ultrasound-targeted microbubble destruction technology has become an effective and non-invasive anti-tumor therapy for deep tumors.It can enhance the efficacies of chemotherapy,gene therapy,immunotherapy,and anti-angiogenic therapy by improving cell membrane permeability and destroying tumor neovasculature.It can be applied to sonodynamic therapy and realize multimodal synergistic therapy on the basis of nanoparticles,which increases the anti-tumor efficiency and offers a promising target therapy for tumors.
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Humans , Contrast Media , Genetic Therapy , Microbubbles , Neoplasms , UltrasonographyABSTRACT
Objective@#To investigate the effects of modified acidic fibroblast growth factor (MaFGF) mediated by nanoliposomes combined with ultrasound-targeted microbubble destruction (UTMD) on left ventricular systolic function in early diabetes mellitus(DM) rats.@*Methods@#The nanoliposomes containing MaFGF(MaFGF-nlip) were prepared by reverse phase evaporation method. Among 60 male Sprague Dawley (SD) rats, 50 rats were randomly selected and were induced to be DM models by streptozotocin(STZ) through intraperitoneal injecting, the other 10 rats as control group. Then DM rats were randomly divided into 4 groups: DM model group, MaFGF solution group, MaFGF-nlip group and MaFGF-nlip+ UTMD group. After the successful induction of DM model, the intervention was performed twice a week.After 12 weeks of intervention, all rats underwent conventional echocardiography and velocity vector imaging (VVI). Left ventricular ejection fraction (LVEF) and left ventricular fraction shortening(LVFS) were measured by conventional echocardiography. The mean peak systolic radial velocity (Vs), radial strain (Sr) and radial strain rate (SRr) of six walls at the papillary muscle level were measured in left ventricular short-axis view by VVI. At last, myocardial tissue of all rats were stained with Sirius red to evaluate myocardial interstitial fibrosis. The level of myocardial apoptosis was evaluated by TUNEL staining, and the changes of myocardial ultrastructure were observed by transmission electron microscopy.@*Results@#The prepared MaFGF-nlip were more rounded, evenly dispersed, and of good stability and high encapsulation efficiency. Twelve weeks later after intervention, LVEF, LVFS, Vs, Sr and SRr in the DM model group were significantly lower than those in the control group (all P<0.05). LVEF, LVFS, Vs, Sr and SRr in the MaFGF-nlip+ UTMD group were significantly higher than those of the DM model group and other intervention groups (all P<0.05). The results of Sirius red staining and Tunel staining showed that CVF and AI in the DM model group were significantly higher than those in the control group (all P<0.05). For MaFGF-nlip+ UTMD group, CVF and AI were significantly decreased compared with the DM model group and other intervention groups(all P<0.05). According to the results of transmission electron microscopy, compared with the DM model group, the improvement of myocardial ultrastructure was the most obvious in the MaFGF-nlip+ UTMD group.@*Conclusions@#MaFGF delivered by using nanoliposomes combined with UTMD can improve the left ventricular systolic function in diabetic rats by inhibiting the myocardium cardiac fibrosis and reducing the cardiomyocyte apoptosis.
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Introduction: We examined the thermophysiological effects of ultrafine bubble (UB) bathing in comparison with microbubble (MB) and freshwater (FW) bathing. Subjects and Methods: Seven healthy women aged 35.6±2.9 years provided informed consent to participate in the study. After a 10-min rest, each subject engaged in UB, MB, and FW bathing (on separate days) at 40°C for 10 min. During the experiment, tympanic temperature, local sweat rate, local skin temperature, heat flow, and heart rate variability were continuously recorded. Subjective assessments of thermal sensation and comfort were rated on a visual analog scale between 0 to 100. Results: Increases in tympanic temperature and mean body temperature were highest during MB bathing, and similar increases were observed during UB and FW bathing. Local sweating was highest during MB bathing and lowest during UB bathing. A significant interaction was observed between local sweating during bathing and bathing style (P<0.001). The increase in local sweat rate relative to body temperature was lowest during UB bathing and highest during MB bathing. Discussion: During UB bathing, UBs and MBs that were generated in high concentrations in the bathtub decreased the flow of heat to the body, thereby suppressing an increase in tympanic temperature and yielding the lowest local sweat late. However, during MB bathing, in which a moderate concentration of UBs and MBs were generated, the increase in heat flow due to the convection of hot water exceeded the decrease in heat flow due to the bubbles. Conclusions: The results suggest that bubble properties and convection characteristics altered the balance of heat flow, leading to differences in the thermoregulatory response during and after bathing.
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Objective • To investigate the effect of 500 kHz pulsed ultrasound combined with SonoVue microbubbles on the vascular permeability of hind limbs in rats and the permeability dynamics for the duration. Methods • Eighty male Sprague Dawley rats were randomly divided into eight groups (n=10), including control group, only microbubble group (MB group), and microbubble combined with ultrasound groups (MB+US group). And MB+US groups classified into time subgroups according to the interval from the endpoint of ultrasound exposure to the injection of Evans blue (EB), included 2.5 min group, 5 min group, 10 min group, 20 min group, 30 min group and 60 min group. The change of vascular permeability was quantitively analyzed by detecting the content of EB after ultrasound irradiation. Meanwhile, four rats in each group were randomly selected. Two of them were performed hematoxylin-eosin (H-E) staining; and the rest of them underlied transmission electron microscope analysis. Results • The results of EB content detected from muscle samples demonstrated that the exposure of ultrasound in conjunction with microbubbles could alter the vascular permeability of hind limbs of rats. The optimal time window for extravasation was within 30 min after ultrasound exposure. And the permeability could return to the normal status 60 min after ultrasound irradiation. There was no apparent damage on arteries and muscles in the slices with H-E staining. From the observation of transmission electron microscope, the tight junctions between endothelial cells on the arterial wall were significantly widened in MB+US groups. Conclusion • The application of ultrasound with the frequency of 500 kHz combined with SonoVue microbubbles can reversibly change the vascular permeability of hind limbs in rats without obvious damage to the tissues.
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Objective To assess the role of activated platelets in the inflammatory procession of atherosclerosis(AS)by ultrasound molecular imaging.Methods Sixty ApoE-/-mice were fed with high fat diet to establish AS model as experimental group,and 40 C57BL/6J mice were fed with normal diet as control group.Biotin-avidin bridging method was used to construct platelet-targeted microbubbles with recombinant vWF-A1 domain (Mb-A1),microbubbles carrying monoclonal antibodies to VCAM-1 (Mb-VCAM1)and microbubbles carrying IgG monoclonal antibody(Mb-ctrl).In vitro and in vivo experiments were carried out to evaluate the ability of Mb-A1 to target platelets on vascular endothelial surface.Contrast enhanced ultrasound molecular imaging of proximal ascending aorta was performed with Mb-A1 ,Mb-VCAM1 and Mb-ctrl.The expression and distribution of platelets and monocytes/macrophages on the endothelium of ascending aorta of AS mice were observed and analyzed by immunofluorescence staining. Results ①A large number of Mb-A1 adhering to the surface of activated platelets coated in Petri dishes were observed under fluoresce.②After platelet immune-depletion in 30-week AS mice,the signal intensity of Mb-A1 decreased significantly in ascending aorta,while that of Mb-ctrl has no obvious change(P <0.05).③In ApoE-/-mice,signals from platelet targeted microbubbles increased from 8 to 32 weeks of age in ApoE-/-mice,which coincided with the increase of signals from VCAM-1 targeted microbubbles(P <0.05).④Activated platelets on the endothelial surface of ascending aorta increased progressively with age from 8 weeks,and partly overlapped with the distribution of monocytes/macrophages.Conclusions Platelets contribute to the initiation and progression of atherosclerosis as an inflammatory mediator through the interaction with vascular endothelium.
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Objective To analyze the specificity and sensitivity of the modified microbubble test in identifying the peripherally inserted central venous catheters (PICC) tip based on the chest X-ray location as the"gold standard", and to find out an accurate and noninvasive PICC tip positioning method that can save time and cost. Methods Convenient sampling method was conducted. The patients under PICC guided by ultrasound in intensive care unit (ICU) or PICC clinic of the First Affiliated Hospital of Nanchang University from August 2017 to February 2018 were enrolled. All patients were followed up by ultrasound guided PICC catheter placement, modified microbubble test and chest X-ray localization. The relationship between the density of microbubbles in modified microbubble test and the location of PICC tip in chest X-ray localization was analyzed. Using chest X-ray localization as the "gold standard", the diagnostic evaluation indexes such as specificity and sensitivity of PICC tip identification by modified microbubble test were calculated. Results A total of 120 patients were enrolled during the study period, excluding those who refused to participate in the study, unclear right atrial ultrasound, conscious intolerance, unclear chest X-ray, and finally 108 patients completed the modified microbubble test and chest X-ray tip localization. According to the chest X-ray localization results of 108 patients, 69 patients (63.9%) were in ideal locations, 33 (30.6%) were in dissatisfactory position, and 6 (5.5%) were in malposition. There was no significant difference in gender, age, tube placement, depth of catheterization, placement of catheterization room, and catheterization among the three groups. In the modified microbubble test, there were 74 patients (68.5%) with gradeⅠmicrobubble, 25 (23.2%) with gradeⅡmicrobubble, and 9 (8.3%) with grade Ⅲ microbubble. There was a correlation between microbubble density and the tip position of the catheter, showing a moderate intensity correlation, and the contingency coefficient was 0.662. The sensitivity of the modified microbubble test for PICC tip positioning was 95.7% (66/69), the specificity was 89.7% (35/39), the rate of missed diagnosis was 4.4% (3/69), the misdiagnosis rate was 10.3% (4/39), the positive predictive value was 94.3% (66/70), the negative predictive value was 92.1% (35/38), and the Youden index was 0.85. The consistency between the two methods was good, and the Kappa value was 0.86. Conclusions Compared with the chest X-ray localization method, the modified microbubble test method has high sensitivity and specificity in identifying PICC in the position, and the operation is simple, noninvasive, with less time and low cost. The modified microbubble test can be used as a screening test for PICC tip position, especially in ICU. When there are technical limitations or suspicious patient, further chest X-ray is necessary.
ABSTRACT
Objective@#To analyze the specificity and sensitivity of the modified microbubble test in identifying the peripherally inserted central venous catheters (PICC) tip based on the chest X-ray location as the "gold standard", and to find out an accurate and noninvasive PICC tip positioning method that can save time and cost.@*Methods@#Convenient sampling method was conducted. The patients under PICC guided by ultrasound in intensive care unit (ICU) or PICC clinic of the First Affiliated Hospital of Nanchang University from August 2017 to February 2018 were enrolled. All patients were followed up by ultrasound guided PICC catheter placement, modified microbubble test and chest X-ray localization. The relationship between the density of microbubbles in modified microbubble test and the location of PICC tip in chest X-ray localization was analyzed. Using chest X-ray localization as the "gold standard", the diagnostic evaluation indexes such as specificity and sensitivity of PICC tip identification by modified microbubble test were calculated.@*Results@#A total of 120 patients were enrolled during the study period, excluding those who refused to participate in the study, unclear right atrial ultrasound, conscious intolerance, unclear chest X-ray, and finally 108 patients completed the modified microbubble test and chest X-ray tip localization. According to the chest X-ray localization results of 108 patients, 69 patients (63.9%) were in ideal locations, 33 (30.6%) were in dissatisfactory position, and 6 (5.5%) were in malposition. There was no significant difference in gender, age, tube placement, depth of catheterization, placement of catheterization room, and catheterization among the three groups. In the modified microbubble test, there were 74 patients (68.5%) with gradeⅠmicrobubble, 25 (23.2%) with gradeⅡ microbubble, and 9 (8.3%) with grade Ⅲ microbubble. There was a correlation between microbubble density and the tip position of the catheter, showing a moderate intensity correlation, and the contingency coefficient was 0.662. The sensitivity of the modified microbubble test for PICC tip positioning was 95.7% (66/69), the specificity was 89.7% (35/39), the rate of missed diagnosis was 4.4% (3/69), the misdiagnosis rate was 10.3% (4/39), the positive predictive value was 94.3% (66/70), the negative predictive value was 92.1% (35/38), and the Youden index was 0.85. The consistency between the two methods was good, and the Kappa value was 0.86.@*Conclusions@#Compared with the chest X-ray localization method, the modified microbubble test method has high sensitivity and specificity in identifying PICC in the position, and the operation is simple, noninvasive, with less time and low cost. The modified microbubble test can be used as a screening test for PICC tip position, especially in ICU. When there are technical limitations or suspicious patient, further chest X-ray is necessary.