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Enhanced Targeting Adhesion Of Targeted Microbubbles By Using Ultrasound Radiation Force

Posted on:2011-12-02Degree:MasterType:Thesis
Country:ChinaCandidate:J LiuFull Text:PDF
GTID:2154360308975008Subject:Medical imaging and nuclear medicine
Abstract/Summary:PDF Full Text Request
Background:The effectiveness of ultrasound (US) microbubble-mediated molecular imaging and drug delivery has significantly affected by the axial laminar flow of vessel, especially the arteries. Microbubble (MB) UCA exhibits a lateral migration toward the vessel axis in laminar flow, preventing microbubble contact with the endothelium. Recently, it was also found that this limitation could be overcome by using a US radiation force (USRF).Objective:In this study, we tried to investigate the abilities of USRF to push microbubble away from central flow and increasing targeted adhesion of circulating targeted microbubble to vessel wall by using different low-amplitude ultrasound radiation forces both in vitro and in vivo. The purpose of this study was to find a set of adaptive USRF parameters, which could be used in molecular imaging and drug delivery.Methods:1. Effect of ultrasound radiation force on microbubble contrast agents with different exposure parametersA capillary flow mimic model was set up for observation and analysis of microbubble displacement and aggregation under stereomicroscope. Investigate the effect of microbubble (MB) contrast agents impacted by different USRF parameters such as acoustic pressure, frequency, duration of exposure, and microbubble concentration under flowing condition.2. USRF promote the targeted MB adhesion in microvasculaturePrepared targeted microbubble contrast agent which take anti-ICAM-1 monoclonal antibody by means of electrostatic adsorption and evaluated its Character. Construction of the cremaster muscle inflammation model by Scrotum injection TNF-a. Fifteen KM mice were randomized into three groups:①only targeted MB group(control group);②targeted MB + 54.2KPa USRF group;③targeted MB + 73.9 KPa USRF group. The UCA adhesion was observed by laser scanning confocal microscopy and determined by green fluorescence area and integrated optical density(IOD) in cremaster microvasculatures.3. USRF promote the targeted MB adhesion in abdominal arteryPrepared targeted microbubble contrast agents which take anti-CD34 monoclonal antibody by means of biotin-streptavidin chemistry and evaluated its Character. For examine the ability of USRF promoting UCA retention in great blood vessel. Nine SD rats were divided in to three groups:①only targeted MB group(control group);②targeted MB + 54.2KPa USRF group;③targeted MB + 73.9KPa USRF group. A bolus of 7×10~7 UCA was injected through tail vein and aorta were insonated immediately after UCA injection according to the grouping. The number of retained UCA was count under electronic scanning microscope. we estimated the condition of UCA adhesion in visual analog scale.Results:1. In vitro studyThe displacement and aggregation of microbubbles occurred significantly at the frequency of 2.0 MHz than 1.0 MHz and 0.5 MHz. Under low acoustic pressure, microbubbles were not visually disrupted but the flow slowed down. MB aggregation and deflection in the tube happened at the MB concentration of 7×10~7/ml but it was not when the concentration rose to 7×10~9/ml because of the high viscosity. The ultrasound exposure time could not affect significantly in displacement and MB aggregation.2. In vivo study on mouse cremaster microvasculatureMicrobubbles carried anti-ICAM-1 monoclonal antibody has been successfully prepared. The diameter of ICAM-1 MB was between 1 to 10μm, with 90% below 3.25μm and the Concentration of it was 107 /ml. The antibody carrying rate of MB was about 75%. The mean fluorescence area in microvascular of control group was 78.0±35.8μm~2, the IOD was 2342.7±1053.1. However, The mean fluorescence area in 52.4KPa and 73.9KPa USRF group were 422.8±91.3μm~2 and 1522.0±464.2μm~2, the IOD were 9618.9±2522.0 and 42123.1±20001.4. There were significant difference between 73.9KPa USRF group and control group using spss13.0 one-way ANOVA test for statistical analysis. The area of green fluorescence are approximately seventeen-fold increase in 73.9KPa group relative to that in control group, and the IOD was twenty-fold in 73.9KPa group compared to the control group.3. In vivo study on rat abdominal arteryMicrobubbles carried anti-CD34 monoclonal antibody has been prepared successfully. The diameter of UCA was between 1 and 8μm, with 90% below 2.96μm and the Concentration of 107 /ml. The antibody carrying rate of MB was about 70%. The mean visual score of control group was 0.467±0.507, and in 52.4KPa USRF group was 1.067±0.785. Contrary to control group, There were a large number of microbubbles attached to the vascular endothelial in 73.9KPa USRF group. Microbubbles were piled layer upon layer and have a tendency of aggregation.Conclusion:1. Microbubble contrast agents could be manipulated under some ultrasound parameters. It is expected to physically modulated in blood vessels and helped in targeted adhesions for many therapeutic purposes.2. USRF can promote the targeted MB adhesion in microvasculatures and the targeting enhanced significantly at a higher acoustic pressure of 79.3 KPa.3. USRF can be more effective in the large blood vessels to against the shear force generated by axial flow. Substantial targeted retention was observed in the absence of acoustic treatment at a higher acoustic pressure of 79.3 KPa.
Keywords/Search Tags:Ultrasound radiation force, Targeted microbubble, Targeted adhesion, Molecular imaging, Drug or gene delivery
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