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Tumor Microcirculation Obstructed by Microbubbles Mediated Ultrasound Cavitation

Author: LiPei
Tutor: LiuZheng
School: Third Military Medical University
Course: Medical Imaging and Nuclear Medicine
Keywords: Microbubble Pusled high intensity focused ultrasound Mesentery vessel VX2 Tumor
CLC: R73-36
Type: Master's thesis
Year: 2007
Downloads: 84
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Abstract


Background:Tumor angiogenesis is critical for growth and metastasis of solid tumors. Anti-angiogenesis is a new strategy in cancer therapy following surgery,chemotherapy and radiotherapy.However,the existing methods usually strike or inhibit the specific target of tumor angiogenesis and this may have certain side effects.The related physical treatment for tumor angiogenesis has not been reported.Microbubbles ultrasound contrast agent(UCA) can generate significant physical effects from cavitation under ultrasound emission.The mechanical effects released from cavitation(non-thermal effects) are potentially able to erode targeted living tissues.This makes it possible to disrupt the defective tumor microvasculature.In addition,ultrasound cavitations could happen at relatively lower ultrasound intensity,and this prevents the thermal side effects of high intensity focused ultrasound.Objective:This study is trying to explore the vascular effects induced by microbubbles mediated pulsed high intensity focused ultrasound(HIFU).It is supposed that vascular wall might be disrupted by mechanical effects of cavitation,resulting in vascular thrombosis or gas embolism.This new method could be a potential noninvasive physical therapy of malignancy.Methods:1.MaterialsUltrasound Instruments:the specific designed pulsed high-intensity focused ultrasound device;Diagnostic ultrasound imaging system:GE Logic 9 ultrasound system with 9L probe.Microbubbles:Zhifuxian,a perfluoropentene filled lipid microbubbles with bubble concentration at 7×10~9/ml,average 2μm in diameter,and 98%of the MBs less than 8μm.Animals:73 healthy New Zealand rabbits,40 New Zealand rabbits bearing subcutaneous VX2 tumor,weighing from 2.0 to 2.5 kg,were included.2.Methods: (1) Impact of intermittent interval on microvascular damage induced by microbubbles mediated ultrasound cavitation32 New Zealand rabbits were randomly divided into 4 groups for the factors including microbubbles,ultrasound and ultrasound delivery modes.Pulsed focused ultrasound with a peak negative pressure of 2.6 MPa was delivered directly to mesentery vessels followingⅣof lipid microbubbles at 0.1 ml/kg.Hematoma happened around the vessels immediately when the insonation began.It was then grossly measured in size then sent for pathological examination.(2) Impacts of microbubbles dose,ablation duration and peak acoustic pressure on the vascular effects33 New Zealand rabbits were divided into 11 groups randomly for different MB dosages,ablation duration and peak acoustic pressures.The small mesentery arteriovenous vessels were carefully aimed and insonated by pulsed focused US.Hematoma around the vessels was quickly formed and measured in size.It was later sent for electron microscopy and light microscopy.(3) Obstruction of subcutaneous VX2 tumor microcirculation induced by microbubbles mediated ultrasound cavitation40 rabbits bearing subcutaneous VX2 tumor were divided into 3 groups randomly for the factors including microbubbles and ultrasound.Focused ultrasound was delivered directly to tumor surface for 10 minutes following intravenous infusion of microbubbles at 0.2 ml/kg in the experimental groups.The control groups were applied only US or saline injection.The tumor perfusion after US ablation was then imaged using contrast ultrasonography at 0 min,30 mins,60 mins and 24 hours.VX2 tumor samples were then sent for routine pathological examination.Results:1.Test of intermittent ultrasonic emission:gross visual hematoma and thrombosis were developed in both the intermittent US delivery mode and the continuous mode.However, the intermittent mode produced larger hematoma(58.2±8.1 vs.21.4±8.8 mm~2,P＜0.01) and more significant microscopic damage than that of the continuous mode.Severe red blood cell extrusion,endothelial malformation,wall discontinuity or rupture of artery wall and thrombus embolism were found in both experimental groups under microscopy.The damage was more serious in veins where thrombi usually blocked the lumen. 2.Impact of microbubbles doses,peak acoustic pressures and irradiation duration on vascular effects:On microbubbles dosage,hematoma enlarged significantly related with increasedⅣof microbubbles doses.The average hematoma size rose from 0 to 75.5±11.3 mm~2.On irradiation time,hematoma enlarged significantly along with irradiation time prolonged,and also the average hematoma size increased from 0 to 76.5±5.3 mm~2.Although the impact of peak acoustic pressure did not show a statistical difference on hematoma,the average size increased from 38.7±14.7 to 58.2±8.1 mm~2(p＞0.05).Gross regional hematoma around the small arteriovenous vessels was formed in the experimental groups.Massive extravasations of red blood cells leaking out from vessels, malformation and drop-off of endothelium,thrombosis could be found under light microscopy.In some serious cases,the lumen was blocked by thrombi.Greater vascular wall damage usually happened on one side than that of the opposite side.Under electron microscope,wall damages like endothelial cell drop-off,elastic layer discontinuity and tissue debris,were related to the increases of microbubbles and irradiation time.3.Blockage of VX2 tumor microcirculation:The gray scale value(GSV) of tumor contrast perfusion remained before and after treatment(P＞0.05) in both the simple microbubbles and the simple US group.The VX2 tumor contrast perfusion imaging was opacified with an average GSV of 84.1±22.4 and it almost vanished in the two experimental groups immediately after treatment.At 0 min,30 min,60 min post treatment, the contrast perfusion GSV gradually increased from 15.8±10.8(0 min),30.1±21.3(30 min),45.4±29.8(60 min) to 46.9±22.3(24 h).The tumor angiogenesis perfusion displayed a gradually recanalization or restoration.All the other normal vessels in the surrounding tissues remained intact in US contrast perfusion imaging.Conclusions:This preliminary study indicated ultrasound is able to make non-thermal mechanically damages to the mesentery small vessels when coordinated with microbubbles.The intermittent mode can induce more severe vascular effects than that of the continuous mode. The VX2 tumor minicirculation can be selectively blocked by microbubbles mediated ultrasound cavitation,but the mechanism remained unknown.

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