微泡增强的超声空化抑制兔VX_2肿瘤生长和转移的实验研究
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摘要
背景
实体肿瘤的生长、转移依赖肿瘤新生血管生成,一旦新生血管长入肿瘤,有充分的血液供应,肿瘤组织将得到快速生长并难以控制。抗肿瘤血管生成治疗已成为继化疗和放疗之后的一种新型治疗模式。然而,目前已发现的抗肿瘤血管生成方法,几乎都是采用化学或者生物药物攻击肿瘤新生血管的特异性生物学靶点,有一定副作用,治疗效果并不理想。本实验前期研究发现,通过静脉注射脂质造影剂微泡联合脉冲式聚焦超声直接作用兔皮下VX2肿瘤区域,微泡增强的超声空化效应可以选择性阻断肿瘤微血管,而周边正常血管未见受到显著影响。
目的
本研究在前期微泡增强的超声空化损伤肿瘤微血管的基础上,采用兔VX2皮下移植性肿瘤作为研究对象,目的是探讨微泡增强的超声空化对肿瘤的生长抑制作用及对肿瘤转移的影响。
材料和方法
1.主要实验材料
实验仪器:本实验室自行研制的小型脉冲式聚焦超声治疗仪,治疗头频率1.2 MHz,峰值声压4.6MPa,声强0.89 W/cm2。GE公司Logiq 9型彩色多普勒超声仪,9L高频探头,频率5～9 MHz,配有编码谐波超声造影模式。
脂质微泡:本科实验室研制的“脂氟显”脂质微泡,核心气体为全氟丙烷,外观呈乳白色凝乳状,平均粒径2μm,其中98﹪<8μm,浓度约为4-9×109/ ml。
速眠新Ⅱ注射液:为二甲苯胺噻唑、乙二胺四乙酸、盐酸二氢埃托啡和氟哌啶醇组成的复方制剂,军事医学科学院军事兽医研究所研制。
实验动物:健康新西兰白兔30只,雌雄不限,体质量2.0～2.5 kg,由新桥医院动物实验中心提供。VX2肿瘤组织匀浆由重庆医科大学医学超声工程研究所提供。
2.实验程序
(1)30只移植有皮下VX2肿瘤的新西兰大白兔,随机分为超声微泡治疗组,单纯超声组和超声假照组进行实验研究。经静脉注射脂质微泡的同时,脉冲式聚焦超声直接辐照肿瘤区域。单纯超声组和假照组分别用5ml生理盐水和超声假照替代,每次10分钟,每隔72小时治疗一次,采集各时间点肿瘤二维超声图像和超声造影影像,测量肿瘤切面最大长径、短径。
(2)第30天观察时间点,超声造影后即刻处死并解剖实验兔,观察肺、肝脏、肾脏、盆腔淋巴结有无转移灶。
3.数据分析
肿瘤生长抑制以肿瘤直径和体积为观察指标,采用SPSS 13.0统计学处理软件,肿瘤大小用x±s表示;治疗前各组肿瘤直径、体积及治疗后各组肿瘤直径大小比较采用单因素方差分析(Oneway ANOVA);治疗后各时间点肿瘤体积大小比较采用Kruskal-Wallis分析方法;肿瘤转移灶按转移个数分为0-3级,组间比较采用秩和检验做半定量分析。以P<0.05为差异有统计学意义。
结果
(1)兔VX2肿瘤生长抑制结果:兔VX2肿瘤在30天的实验周期内,微泡超声治疗组、单纯超声组和超声假照组的肿瘤平均直径,从1.1±0.1cm、1.2±0.2cm、1.2cm±0.1cm生长至1.7±0.3cm、3.4±0.7cm、3.6±0.8cm;三组的平均体积从0.4±0.2cm3、0.6±0.3cm3、0.5±0.2cm3生长至4.5±3.1cm3、35.1±46.7cm3、48.2±44.3cm3、微泡超声治疗组肿瘤直径、体积明显小于另两组(P﹤0.05)。单纯超声组和假照组,肿瘤直径和体积比较无显著差异(P﹥0.05)。
(2)兔VX2肿瘤转移情况:微泡超声治疗组肿瘤转移情况评分多为0-1级;而单纯超声组和假照组评分多为2-3级,微泡超声治疗组与单纯超声组、假照组相比,在肺和肾脏的转移灶数量呈明显下降趋势(P﹤0.05),但在肝脏和盆腔淋巴结肿瘤转移方面无显著差异(P﹥0.05)。
结论
超声空化治疗在反复多次阻断肿瘤微循环的基础上,产生了一定程度的肿瘤生长抑制作用,并在一定程度上减少了肿瘤转移的发生。
Background:
Tumor angiogenesis is critical and essential in tumor growth and metastasis. Once the neovasculature is builded up to provide enough nutrition, tumor growth would become inevitable. Anti-angiogenesis therapy has been accepted as an new anti-tumor strategy. Nowadays, almost all of the anti-angiogenesis approaches take advantage of using chemical or biological drugs to attack specific receptor targets on angiogenesis. It is featured with insufficient therapeutic effect and some side-effects.
This study is based on our previous findings that MBs enhanced ultrasound cavitation could selectively disrupt the microvasculature of rabbit VX2 tumor resulting in tumor circulation blockage.
Objective:
The purpose of this study is to investigate effects of MBs enhanced ultrasound cavitation on tumor growth and metastasis inhibition in a VX2 tumor model of rabbit.
Materials and Methods:
(1) Materials:
Therapeutic ultrasound instrument: specific designed pulsed focused ultrasound (PFUS) devices, with the transducers frequency of 1.2 MHz, adjustable duty cycle and peak acoustic pressure.
Diagnostic ultrasound imaging system: GE Logiq 9 ultrasound system, 9L probe, eligible to perform contrast enhanced ultrasonography (CEUS) with low MI. Microbubbles: Zhifuxian, a perfluoropropane filled lipid MB, with bubbles concentration of 4~9×109/ml, average 2μm in diameter, and 98% of the MBs less than 8μm in diameter.
(2) Methods: Thirty New Zealand white rabbits bearing subcutaneous VX2 tumor were randomly divided into 3 groups for the impact factors including microbubbles (MB) and ultrasound (US). Pulsed focused ultrasound was delivered directly to the tumor surface for 10 minutes during intravenous infusion of microbubbles in the experimental (US+MB) group. The two control groups were applied with either ultrasound exposure (US) or saline injection (SHAM). The procedure was repeated every 72 hours until the 30th day. Contrast enhanced US and grey scale ultrasonography were acquired after every treatment to get the tumor perfusion images, size and volume measurements.
At the end of the experiment, gross inspection and counting of tumor metastatic lesions at lung, liver, kidney and pelvic lymph nodes were performed following the animal sacrifice. The VX2 tumor metastasis was classified into 0-3 grade according to the counting number of meatastic lesions.
Results:
The average tumor volume of the US+MB, US, and the SHAM groups at the baseline were 0.4±0.2cm3,0.6±0.3cm3,0.5±0.2cm3 respectively. It grew to 4.5±3.1cm3,35.1±46.7cm3,48.2±44.3cm3 within a 30d experimental period, respectively. The average tumor volume of the US+MB group was significantly smaller than that of the two control groups at the end of experiment(P﹤0.05). The VX2 tumor metastatic counting also showed significant declines at lung and kidney in the experimental group(P﹤0.05). Conclusions:
Multiple MBs enhanced ultrasound cavitation therapy can induce growth inhibition of VX2 tumor. It is also able to reduce VX2 tumor metastasis in lung and kidney.
实体肿瘤的生长、转移依赖肿瘤新生血管生成,一旦新生血管长入肿瘤,有充分的血液供应,肿瘤组织将得到快速生长并难以控制。抗肿瘤血管生成治疗已成为继化疗和放疗之后的一种新型治疗模式。然而,目前已发现的抗肿瘤血管生成方法,几乎都是采用化学或者生物药物攻击肿瘤新生血管的特异性生物学靶点,有一定副作用,治疗效果并不理想。本实验前期研究发现,通过静脉注射脂质造影剂微泡联合脉冲式聚焦超声直接作用兔皮下VX2肿瘤区域,微泡增强的超声空化效应可以选择性阻断肿瘤微血管,而周边正常血管未见受到显著影响。
目的
本研究在前期微泡增强的超声空化损伤肿瘤微血管的基础上,采用兔VX2皮下移植性肿瘤作为研究对象,目的是探讨微泡增强的超声空化对肿瘤的生长抑制作用及对肿瘤转移的影响。
材料和方法
1.主要实验材料
实验仪器:本实验室自行研制的小型脉冲式聚焦超声治疗仪,治疗头频率1.2 MHz,峰值声压4.6MPa,声强0.89 W/cm2。GE公司Logiq 9型彩色多普勒超声仪,9L高频探头,频率5～9 MHz,配有编码谐波超声造影模式。
脂质微泡:本科实验室研制的“脂氟显”脂质微泡,核心气体为全氟丙烷,外观呈乳白色凝乳状,平均粒径2μm,其中98﹪<8μm,浓度约为4-9×109/ ml。
速眠新Ⅱ注射液:为二甲苯胺噻唑、乙二胺四乙酸、盐酸二氢埃托啡和氟哌啶醇组成的复方制剂,军事医学科学院军事兽医研究所研制。
实验动物:健康新西兰白兔30只,雌雄不限,体质量2.0～2.5 kg,由新桥医院动物实验中心提供。VX2肿瘤组织匀浆由重庆医科大学医学超声工程研究所提供。
2.实验程序
(1)30只移植有皮下VX2肿瘤的新西兰大白兔,随机分为超声微泡治疗组,单纯超声组和超声假照组进行实验研究。经静脉注射脂质微泡的同时,脉冲式聚焦超声直接辐照肿瘤区域。单纯超声组和假照组分别用5ml生理盐水和超声假照替代,每次10分钟,每隔72小时治疗一次,采集各时间点肿瘤二维超声图像和超声造影影像,测量肿瘤切面最大长径、短径。
(2)第30天观察时间点,超声造影后即刻处死并解剖实验兔,观察肺、肝脏、肾脏、盆腔淋巴结有无转移灶。
3.数据分析
肿瘤生长抑制以肿瘤直径和体积为观察指标,采用SPSS 13.0统计学处理软件,肿瘤大小用x±s表示;治疗前各组肿瘤直径、体积及治疗后各组肿瘤直径大小比较采用单因素方差分析(Oneway ANOVA);治疗后各时间点肿瘤体积大小比较采用Kruskal-Wallis分析方法;肿瘤转移灶按转移个数分为0-3级,组间比较采用秩和检验做半定量分析。以P<0.05为差异有统计学意义。
结果
(1)兔VX2肿瘤生长抑制结果:兔VX2肿瘤在30天的实验周期内,微泡超声治疗组、单纯超声组和超声假照组的肿瘤平均直径,从1.1±0.1cm、1.2±0.2cm、1.2cm±0.1cm生长至1.7±0.3cm、3.4±0.7cm、3.6±0.8cm;三组的平均体积从0.4±0.2cm3、0.6±0.3cm3、0.5±0.2cm3生长至4.5±3.1cm3、35.1±46.7cm3、48.2±44.3cm3、微泡超声治疗组肿瘤直径、体积明显小于另两组(P﹤0.05)。单纯超声组和假照组,肿瘤直径和体积比较无显著差异(P﹥0.05)。
(2)兔VX2肿瘤转移情况:微泡超声治疗组肿瘤转移情况评分多为0-1级;而单纯超声组和假照组评分多为2-3级,微泡超声治疗组与单纯超声组、假照组相比,在肺和肾脏的转移灶数量呈明显下降趋势(P﹤0.05),但在肝脏和盆腔淋巴结肿瘤转移方面无显著差异(P﹥0.05)。
结论
超声空化治疗在反复多次阻断肿瘤微循环的基础上,产生了一定程度的肿瘤生长抑制作用,并在一定程度上减少了肿瘤转移的发生。
Background:
Tumor angiogenesis is critical and essential in tumor growth and metastasis. Once the neovasculature is builded up to provide enough nutrition, tumor growth would become inevitable. Anti-angiogenesis therapy has been accepted as an new anti-tumor strategy. Nowadays, almost all of the anti-angiogenesis approaches take advantage of using chemical or biological drugs to attack specific receptor targets on angiogenesis. It is featured with insufficient therapeutic effect and some side-effects.
This study is based on our previous findings that MBs enhanced ultrasound cavitation could selectively disrupt the microvasculature of rabbit VX2 tumor resulting in tumor circulation blockage.
Objective:
The purpose of this study is to investigate effects of MBs enhanced ultrasound cavitation on tumor growth and metastasis inhibition in a VX2 tumor model of rabbit.
Materials and Methods:
(1) Materials:
Therapeutic ultrasound instrument: specific designed pulsed focused ultrasound (PFUS) devices, with the transducers frequency of 1.2 MHz, adjustable duty cycle and peak acoustic pressure.
Diagnostic ultrasound imaging system: GE Logiq 9 ultrasound system, 9L probe, eligible to perform contrast enhanced ultrasonography (CEUS) with low MI. Microbubbles: Zhifuxian, a perfluoropropane filled lipid MB, with bubbles concentration of 4~9×109/ml, average 2μm in diameter, and 98% of the MBs less than 8μm in diameter.
(2) Methods: Thirty New Zealand white rabbits bearing subcutaneous VX2 tumor were randomly divided into 3 groups for the impact factors including microbubbles (MB) and ultrasound (US). Pulsed focused ultrasound was delivered directly to the tumor surface for 10 minutes during intravenous infusion of microbubbles in the experimental (US+MB) group. The two control groups were applied with either ultrasound exposure (US) or saline injection (SHAM). The procedure was repeated every 72 hours until the 30th day. Contrast enhanced US and grey scale ultrasonography were acquired after every treatment to get the tumor perfusion images, size and volume measurements.
At the end of the experiment, gross inspection and counting of tumor metastatic lesions at lung, liver, kidney and pelvic lymph nodes were performed following the animal sacrifice. The VX2 tumor metastasis was classified into 0-3 grade according to the counting number of meatastic lesions.
Results:
The average tumor volume of the US+MB, US, and the SHAM groups at the baseline were 0.4±0.2cm3,0.6±0.3cm3,0.5±0.2cm3 respectively. It grew to 4.5±3.1cm3,35.1±46.7cm3,48.2±44.3cm3 within a 30d experimental period, respectively. The average tumor volume of the US+MB group was significantly smaller than that of the two control groups at the end of experiment(P﹤0.05). The VX2 tumor metastatic counting also showed significant declines at lung and kidney in the experimental group(P﹤0.05). Conclusions:
Multiple MBs enhanced ultrasound cavitation therapy can induce growth inhibition of VX2 tumor. It is also able to reduce VX2 tumor metastasis in lung and kidney.
引文
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5.马亚军,钱晓萍,刘宝瑞等.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
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1. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
2.乔虹.肿瘤的抗血管生成疗法.国外医学(药学分册). 2006. 33(5): 329-330,335.
3.马亚军,钱晓萍,刘宝瑞等.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
4.高顺记,李佩倞,赵洋等.微泡增强的超声空化阻断肿瘤微循环的初步研究.中国超声医学杂志. 2010. 26(2): 110-112.
5.李秋颖,刘政,李佩惊等.微泡介导下脉冲式聚焦超声空化导致血管损伤的实验研究.中国超声医学杂志. 2008. 24(4): 297-299.
6.李佩倞,左松,刘政等.间歇式发射对微泡超声空化损伤小血管的增强作用.临床超声医学杂志. 2007. 9(10): 577-580.
7. Liu Z, Li P, Li QY, et al. Impact of microbubbles mediated ultrasound cavitation on VX2 tumor microcirculation. The 8th International Symposium on Therapeutic Ultrasound. 2008 : 86.
8. Rhee TK, Larson AC, Prasad PV, et al. Feasibility of blood oxygenation level-dependent MR imaging to monitor hepatic transcatheter arterial embolization in rabbits. J Vasc Interv Radiol. 2005. 16(11): 1523-1528.
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13.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
1. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
2.王晓莉,黄倩.肿瘤血管新生的机制及研究方向.复旦学报(医学版). 2004. 31(2): 218-220.
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6.钟华,李锐,郝迎学等.超声空化效应对肿瘤细胞迁移运动影响的实验研究.中国超声医学杂志.2008.24(2):97-99.
7.高顺记,李佩倞,赵洋等.微泡增强的超声空化阻断肿瘤微循环的初步研究.中国超声医学杂志. 2010. 26(2): 110-112.
8. Liu Z, Li P, Li QY, et al. Impact of microbubbles mediated ultrasound cavitation on VX2 tumor microcirculation. The 8th International Symposium on Therapeutic Ultrasound. 2008 : 86.
9.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
1. Gail ter Haar. Is there a "perfect" extracorporeal clinical HIFU device. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
2. Chapelon JY, Blanc E, Lacoste F. Towards more effective HIFU treatments. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
3.潘春华,罗荣城.高强度聚焦超声治疗肿瘤原理及应用原则.中国肿瘤. 2003. 12(9): 530-533.
4.乔虹.肿瘤的抗血管生成疗法.国外医学(药学分册). 2006. 33(5): 329-330,335.
5.马亚军,钱晓萍,刘宝瑞.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
6. Gramiak R,Shah PM, Kramer DH. Ultrasound cardiography: contrast studies in anatomy and function. Radiology, 1969.92(5):939-948.
7. Hohmann J, Albrecht T, Hoffmann CW, et al. Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents. Eur J Radiol. 2003. 46(2): 147-159.
8. Albrecht T, Hoffmann CW, Schettler S, et al. Improved detection of liver metastases with phase inversion ultrasound during the late phase of levovist. Acad Radiol. 2002. 9 Suppl 1: S236-S239.
9.刘政,谢峰,王红等.声学造影方法评价兔肝脏VX2肿瘤血管影像增强的实验研究.中国超声医学杂志. 2000. 16(2): 85-87.
10.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
11. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
12. Miller DL, Quddus J. Lysis and sonoporation of epidermoid and phagocytic monolayer cells by diagnostic ultrasound activation of contrast agent gas bodies. Ultrasound Med Biol. 2001. 27(8): 1107-1113.
13.冉海涛,任红,王志刚等.超声波空化效应对体外培养细胞细胞膜作用的实验研究.中华超声影像学杂志. 2003. 12(8): 499-501.
14. Li P, Cao LQ, Dou CY, et al. Impact of myocardial contrast echocardiography on vascular permeability: an in vivo dose response study of delivery mode, pressure amplitude and contrast dose. Ultrasound Med Biol. 2003. 29(9): 1341-1349.
15. Li P, Armstrong WF, Miller DL. Impact of myocardial contrast echocardiography on vascular permeability: comparison of three different contrast agents. Ultrasound Med Biol. 2004. 30(1): 83-91.
16. Miller MW, Everbach EC, Cox C, et al. A comparison of the hemolytic potential of Optison and Albunex in whole human blood in vitro: acoustic pressure, ultrasound frequency, donor and passive cavitation detection considerations. Ultrasound Med Biol. 2001. 27(5): 709-721.
17. Koch S, Pohl P, Cobet U, et al. Ultrasound enhancement of liposome-mediated cell transfection is caused by cavitation effects. Ultrasound Med Biol. 2000. 26(5): 897-903.
18. Ward M, Wu J, Chiu JF. Experimental study of the effects of Optison concentration on sonoporation in vitro. Ultrasound Med Biol. 2000. 26(7): 1169-1175.
19. Miller MW, Miller DL, Brayman AA. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol. 1996. 22(9): 1131-1154.
20. Kobayashi N, Yasu T, Yamada S, et al. Endothelial cell injury in venule and capillary induced by contrast ultrasonography. Ultrasound Med Biol. 2002. 28(7): 949-956.
21. Miller DL, Gies RA. The influence of ultrasound frequency and gas-body composition on the contrast agent-mediated enhancement of vascular bioeffects in mouse intestine.Ultrasound Med Biol. 2000. 26(2): 307-313.
22.王雅婕,刘德英,刘政等.超声造影在心脏负荷实验中对心肌微血管的损伤效应.中国超声医学杂志. 2008. 24(2): 106-109.
23. Castensen EL. Mechanisms for biological effects of ultrasound. Proceedings 16th ICA 98. Washington: Seattle, 1998:1437-1438.
24. Liu Y, Uno H, Takatsuki H, et al. Interrelation between HeLa-S3 cell transfection and hemolysis in red blood cell suspension using pulsed ultrasound of various duty cycles. Eur Biophys J. 2005.34(2):163-169.
25. Hwang JH, Brayman AA, Reidy MA, et al. Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound Med Biol. 2005. 31(4): 553-564.
26.李秋颖,刘政,刘德英等.微泡联合纤维蛋白原诱导超声栓塞肠系膜微血管的实验研究.临床超声医学杂志. 2006. 8(8): 449-451.
27.李佩倞,左松,刘政等.间歇式发射对微泡超声空化损伤小血管的增强作用.临床超声医学杂志. 2007. 9(10): 577-580.
28. Yu T, Xiong S, Mason TJ, et al. The use of a microbubble agent to enhance rabbit liver destruction using high intensity focused ultrasound. Ultrasonic Sonochemistry. 2006. 13(2): 143-149.
29. Miller DL, Song J. Tumor growth reduction and DNA transfer by cavitation-enhanced high-intensity focused ultrasound in vivo. Ultrasound Med Biol. 2003. 29(6): 887-893.
30.吴巍,宁新宝,姜藻等.低功率超声辐射LEVOVIST试剂致家兔肝脏微血管栓塞的研究.东南大学学报:自然科学版. 2003. 33(3): 300-302.
31.张航,姜藻,吴巍等.超声辐射微泡剂致肿瘤血管栓塞的实验研究.东南大学学报:医学版. 2004. 23(3): 195-198.
32.郑元义,王志刚,冉海涛等.诊断超声加微泡造影剂对新生血管的作用.中国医学影像技术. 2004. 20(3): 349-351.
33. Roberts WW, Hall TL, Ives K, et al. Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney. J Urol. 2006. 175(2): 734-738.
34. Xu Z, Fowlkes JB, Ludomirsky A, et al. Investigation of intensity thresholds for ultrasound tissue erosion. Ultrasound Med Biol. 2005. 31(12): 1673-1682.
35. Parsons JE, Cain CA, Abrams GD, et al. Pulsed cavitational ultrasound therapy for controlled tissue homogenization. Ultrasound Med Biol. 2006. 32(1): 115-129.
36. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971. 285(21): 1182-1186.
37. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000. 407(6801): 249-257.
38. Kerbel RS. Tumor Angiogenesis. N Engl J Med. 2008. 358(19): 2039-2049.
2. Kong HL, Crystal RG. Gene therapy strategies for tumor antiangiogenesis. J Natl Cancer Inst. 1998. 90(4): 273-286.
3. Nesbit M. Abrogation of tumor vasculature using gene therapy. Cancer Metastasis Rev. 2000. 19(1-2): 45-49.
4.乔虹.肿瘤的抗血管生成疗法.国外医学(药学分册). 2006. 33(5): 329-330,335.
5.马亚军,钱晓萍,刘宝瑞等.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
6. Gail ter Haar. Is there a "perfect" extracorporeal clinical HIFU device. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
7. Chapelon JY, Blanc E, Lacoste F. Towards more effective HIFU treatments. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
8.潘春华,罗荣城.高强度聚焦超声治疗肿瘤原理及应用原则.中国肿瘤. 2003.12(9): 530-533.
9.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
10. Hwang JH, Brayman AA, Reidy MA, et al. Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound Med Biol. 2005. 31(4): 553-564.
11. Parsons JE, Cain CA, Abrams GD, et al. Pulsed cavitational ultrasound therapy for controlled tissue homogenization. Ultrasound Med Biol. 2006. 32(1): 115-129.
12. Xu Z, Fowlkes JB, Ludomirsky A, et al. Investigation of intensity thresholds for ultrasound tissue erosion. Ultrasound Med Biol. 2005. 31(12): 1673-1682.
13.李秋颖,刘政,李佩惊等.微泡介导下脉冲式聚焦超声空化导致血管损伤的实验研究.中国超声医学杂志. 2008. 24(4): 297-299.
14.李佩倞,左松,刘政等.间歇式发射对微泡超声空化损伤小血管的增强作用.临床超声医学杂志. 2007. 9(10): 577-580.
15.高顺记,李佩倞,赵洋等.微泡增强的超声空化阻断肿瘤微循环的初步研究.中国超声医学杂志. 2010. 26(2): 110-112.
16. Liu Z, Li P, Li QY, et al. Impact of microbubbles mediated ultrasound cavitation on VX2 tumor microcirculation. The 8th International Symposium on Therapeutic Ultrasound. 2008 : 86.
1. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
2.乔虹.肿瘤的抗血管生成疗法.国外医学(药学分册). 2006. 33(5): 329-330,335.
3.马亚军,钱晓萍,刘宝瑞等.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
4.高顺记,李佩倞,赵洋等.微泡增强的超声空化阻断肿瘤微循环的初步研究.中国超声医学杂志. 2010. 26(2): 110-112.
5.李秋颖,刘政,李佩惊等.微泡介导下脉冲式聚焦超声空化导致血管损伤的实验研究.中国超声医学杂志. 2008. 24(4): 297-299.
6.李佩倞,左松,刘政等.间歇式发射对微泡超声空化损伤小血管的增强作用.临床超声医学杂志. 2007. 9(10): 577-580.
7. Liu Z, Li P, Li QY, et al. Impact of microbubbles mediated ultrasound cavitation on VX2 tumor microcirculation. The 8th International Symposium on Therapeutic Ultrasound. 2008 : 86.
8. Rhee TK, Larson AC, Prasad PV, et al. Feasibility of blood oxygenation level-dependent MR imaging to monitor hepatic transcatheter arterial embolization in rabbits. J Vasc Interv Radiol. 2005. 16(11): 1523-1528.
9. Eivazi B, Sapundhziev N, Folz BJ, et al. Bipolar radiofrequency induced thermotherapeutic volumetric reduction of VX2 metastases in an animal model. In Vivo. 2005. 19(6): 1023-1028.
10. Haaga JR, Exner AA, Wang Y, et al. Combined tumor therapy by using radiofrequency ablation and 5-FU-laden polymer implants: evaluation in rats and rabbits. Radiology. 2005. 237(3): 911-918.
11. Sapundzhiev N, Dunne AA, Ramaswamy A, et al. The auricular VX2 carcinoma: feasibility of complete tumor resection. Anticancer Res. 2005. 25(6B): 4209-4214.
12. Maruyama H, Matsutani S, Saisho H, et al. Sonographic shift of hypervascular liver tumor on blood pool harmonic images with definity: time-related changes of contrast-enhanced appearance in rabbit VX2 tumor under extra-low acoustic power. Eur J Radiol. 2005. 56(1): 60-65.
13.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
1. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
2.王晓莉,黄倩.肿瘤血管新生的机制及研究方向.复旦学报(医学版). 2004. 31(2): 218-220.
3. Miller DL, Dou C. The potential for enhancement of mouse melanoma metastasis by diagnostic and high-amplitude ultrasound. Ultrasound Med Biol. 2006. 32(7): 1097-1101.
4. Xing Y, Lu X, Pua EC, et al. The effect of high intensity focused ultrasound treatment on metastases in a murine melanoma model. Biochem Biophys Res Commun. 2008.375(4): 645-650.
5. Deng J, Zhang Y, Feng J, et al. Dendritic cells loaded with ultrasound-ablated tumour induce in vivo specific antitumour immune responses. Ultrasound Med Biol. 2010. 36(3): 441-448.
6.钟华,李锐,郝迎学等.超声空化效应对肿瘤细胞迁移运动影响的实验研究.中国超声医学杂志.2008.24(2):97-99.
7.高顺记,李佩倞,赵洋等.微泡增强的超声空化阻断肿瘤微循环的初步研究.中国超声医学杂志. 2010. 26(2): 110-112.
8. Liu Z, Li P, Li QY, et al. Impact of microbubbles mediated ultrasound cavitation on VX2 tumor microcirculation. The 8th International Symposium on Therapeutic Ultrasound. 2008 : 86.
9.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
1. Gail ter Haar. Is there a "perfect" extracorporeal clinical HIFU device. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
2. Chapelon JY, Blanc E, Lacoste F. Towards more effective HIFU treatments. Proceedings in the 5th International Symposium on Therapeutic Ultrasound. 2005, Boston.
3.潘春华,罗荣城.高强度聚焦超声治疗肿瘤原理及应用原则.中国肿瘤. 2003. 12(9): 530-533.
4.乔虹.肿瘤的抗血管生成疗法.国外医学(药学分册). 2006. 33(5): 329-330,335.
5.马亚军,钱晓萍,刘宝瑞.肿瘤抗血管生成生物化疗的研究进展.中华肿瘤防治杂志. 2006. 13(7): 556-559.
6. Gramiak R,Shah PM, Kramer DH. Ultrasound cardiography: contrast studies in anatomy and function. Radiology, 1969.92(5):939-948.
7. Hohmann J, Albrecht T, Hoffmann CW, et al. Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents. Eur J Radiol. 2003. 46(2): 147-159.
8. Albrecht T, Hoffmann CW, Schettler S, et al. Improved detection of liver metastases with phase inversion ultrasound during the late phase of levovist. Acad Radiol. 2002. 9 Suppl 1: S236-S239.
9.刘政,谢峰,王红等.声学造影方法评价兔肝脏VX2肿瘤血管影像增强的实验研究.中国超声医学杂志. 2000. 16(2): 85-87.
10.冯若.超声空化与超声医学.中华超声影像学杂志. 2004. 13(1): 63-65.
11. Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001. 86(1): 23-33.
12. Miller DL, Quddus J. Lysis and sonoporation of epidermoid and phagocytic monolayer cells by diagnostic ultrasound activation of contrast agent gas bodies. Ultrasound Med Biol. 2001. 27(8): 1107-1113.
13.冉海涛,任红,王志刚等.超声波空化效应对体外培养细胞细胞膜作用的实验研究.中华超声影像学杂志. 2003. 12(8): 499-501.
14. Li P, Cao LQ, Dou CY, et al. Impact of myocardial contrast echocardiography on vascular permeability: an in vivo dose response study of delivery mode, pressure amplitude and contrast dose. Ultrasound Med Biol. 2003. 29(9): 1341-1349.
15. Li P, Armstrong WF, Miller DL. Impact of myocardial contrast echocardiography on vascular permeability: comparison of three different contrast agents. Ultrasound Med Biol. 2004. 30(1): 83-91.
16. Miller MW, Everbach EC, Cox C, et al. A comparison of the hemolytic potential of Optison and Albunex in whole human blood in vitro: acoustic pressure, ultrasound frequency, donor and passive cavitation detection considerations. Ultrasound Med Biol. 2001. 27(5): 709-721.
17. Koch S, Pohl P, Cobet U, et al. Ultrasound enhancement of liposome-mediated cell transfection is caused by cavitation effects. Ultrasound Med Biol. 2000. 26(5): 897-903.
18. Ward M, Wu J, Chiu JF. Experimental study of the effects of Optison concentration on sonoporation in vitro. Ultrasound Med Biol. 2000. 26(7): 1169-1175.
19. Miller MW, Miller DL, Brayman AA. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol. 1996. 22(9): 1131-1154.
20. Kobayashi N, Yasu T, Yamada S, et al. Endothelial cell injury in venule and capillary induced by contrast ultrasonography. Ultrasound Med Biol. 2002. 28(7): 949-956.
21. Miller DL, Gies RA. The influence of ultrasound frequency and gas-body composition on the contrast agent-mediated enhancement of vascular bioeffects in mouse intestine.Ultrasound Med Biol. 2000. 26(2): 307-313.
22.王雅婕,刘德英,刘政等.超声造影在心脏负荷实验中对心肌微血管的损伤效应.中国超声医学杂志. 2008. 24(2): 106-109.
23. Castensen EL. Mechanisms for biological effects of ultrasound. Proceedings 16th ICA 98. Washington: Seattle, 1998:1437-1438.
24. Liu Y, Uno H, Takatsuki H, et al. Interrelation between HeLa-S3 cell transfection and hemolysis in red blood cell suspension using pulsed ultrasound of various duty cycles. Eur Biophys J. 2005.34(2):163-169.
25. Hwang JH, Brayman AA, Reidy MA, et al. Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo. Ultrasound Med Biol. 2005. 31(4): 553-564.
26.李秋颖,刘政,刘德英等.微泡联合纤维蛋白原诱导超声栓塞肠系膜微血管的实验研究.临床超声医学杂志. 2006. 8(8): 449-451.
27.李佩倞,左松,刘政等.间歇式发射对微泡超声空化损伤小血管的增强作用.临床超声医学杂志. 2007. 9(10): 577-580.
28. Yu T, Xiong S, Mason TJ, et al. The use of a microbubble agent to enhance rabbit liver destruction using high intensity focused ultrasound. Ultrasonic Sonochemistry. 2006. 13(2): 143-149.
29. Miller DL, Song J. Tumor growth reduction and DNA transfer by cavitation-enhanced high-intensity focused ultrasound in vivo. Ultrasound Med Biol. 2003. 29(6): 887-893.
30.吴巍,宁新宝,姜藻等.低功率超声辐射LEVOVIST试剂致家兔肝脏微血管栓塞的研究.东南大学学报:自然科学版. 2003. 33(3): 300-302.
31.张航,姜藻,吴巍等.超声辐射微泡剂致肿瘤血管栓塞的实验研究.东南大学学报:医学版. 2004. 23(3): 195-198.
32.郑元义,王志刚,冉海涛等.诊断超声加微泡造影剂对新生血管的作用.中国医学影像技术. 2004. 20(3): 349-351.
33. Roberts WW, Hall TL, Ives K, et al. Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney. J Urol. 2006. 175(2): 734-738.
34. Xu Z, Fowlkes JB, Ludomirsky A, et al. Investigation of intensity thresholds for ultrasound tissue erosion. Ultrasound Med Biol. 2005. 31(12): 1673-1682.
35. Parsons JE, Cain CA, Abrams GD, et al. Pulsed cavitational ultrasound therapy for controlled tissue homogenization. Ultrasound Med Biol. 2006. 32(1): 115-129.
36. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971. 285(21): 1182-1186.
37. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000. 407(6801): 249-257.
38. Kerbel RS. Tumor Angiogenesis. N Engl J Med. 2008. 358(19): 2039-2049.