Fe_3O_4纳米磁流体介导的50℃局部热疗对兔VX2肝癌作用的实验研究
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摘要
第一部分兔VX2肝癌模型的建立及超声影像评价
目的:建立兔VX2肝癌模型,探讨该模型的超声影像学表现并进行比较评价,为该模型的应用提供实验依据。
方法:开腹直视下穿刺法将VX2瘤组织块种植于20只日本大耳白兔肝左叶,建立兔肝癌模型。分别于接种后2周、4周行彩色多普勒、能量多普勒及超声造影检查,半定量分级法分别比较三种超声对肿瘤血流检测率的敏感性,每次超声检查后随机处死10只荷瘤兔,测量肿瘤的实际大小取标本进行病理学鉴定,并与超声结果进行对照。
结果:兔肝癌种植成功率为100%,且该法建立的兔VX2肿瘤大小较一致,同期间比较无显著性差异(P＞0.05)。超声与实际测得肿瘤的最大径比较差异无显著性(P＞0.05),两者具有很好的一致性。彩色多普勒、能量多普勒及超声造影均能敏感的检出肿瘤内血流信号,种植2周的小肿瘤以瘤周供血为主,能量多普勒对血流的检出率明显高于彩色多普勒,而种植4周的较大肿瘤血管丰富,表现为瘤周粗大的供瘤血管或散在弥漫分布的点、条状血流,以高速低阻血流为主,彩色多普勒和能量多普勒均显示以三级病灶为主,无显著性差异,种植2周和4周的肿瘤超声造影显示“快进快出”的增强模式,可见完整、细致的肿瘤血管分支及其微小血管。VX2瘤细胞呈团片状或巢状浸润性分布,可见多个核分裂相,与肝实质无明显边界。
结论:瘤组织块穿刺种植法建立的兔VX2肝癌模型复制成功率高且稳定,实验可比性好。超声能有效的监测肿瘤大小及其变化。彩色多普勒和能量多普勒能敏感的检测出肿瘤血流,但能量多普勒对低速血流敏感,尤其是对小肝癌,而超声造影可更有效的反映大小肝癌瘤内微血管分布及血流灌注情况。
第二部分磁流体介导的50℃局部热疗兔VX2肝癌的可行性研究和对肿瘤生长的影响
目的:评估Fe_3O_4纳米磁流体的体内外升温性能,初步评价磁流体局部热疗兔VX2肝癌模型的可行性及其对肿瘤生长的影响。
方法:将纳米磁流体进行透射电镜检测和体外不同电流强度下的升温实验。将接种14天的荷瘤兔随机分为5组:即假治疗对照组(PT组)、生理盐水对照组(NS组)、磁流体对照组(MF组)、磁流体热疗Ⅰ组(MFH1组)、磁流体热疗Ⅱ组(MFH2组)。MFH1组在直接瘤内注射磁流体后立即暴露于交变磁场,50℃加热30min,MFH2组在5天后再重复加热一次。注射磁流体后第1天和第14天进行CT扫描。所有荷瘤兔分别于第一次热疗前和第一次热疗后5天、14天取血检查血常规及肝肾功能。种植后3周热疗组各处死2只实验兔病理学检查,4周后处死所有实验兔,测量肿瘤大小,计算肿瘤的体积抑制率,大体观察标本并进行病理学检查。
结果:磁流体粒径分布尚均匀,10nm左右,有部分聚集。体外磁流体升温速率随电流增大而增大,在电流为100A即磁场强度为47.95Gs时,磁流体先快速上升至70℃后变缓慢最后维持在80℃不上升。磁流体体内可在5～10min内升至50℃,通过手动调节磁场强度可将肿瘤温度控制在相对稳定的范围内50℃±2℃,而正常肝组织和直肠几乎不升温。CT可清晰地显示体内磁流体局限性的高密度影。热疗前后各组间同时间点及同组间不同时间点的血常规、肝肾功能比较均无明显差异(P＞0.05)。种植后4周各组肿瘤最大径分别(4.25±0.68)cm、(4.70±1.12)cm、(4.16±0.88)cm、(2.83±0.51)cm、(2.03±0.34)cm,肿瘤体积分别为(25.82±11.92)cm~3、(32.01±13.14)cm~3、(23.35±12.17)cm~3、(7.43±1.86)cm~3、(2.62±1.35)cm~3。MFH1组和MFH2组的肿瘤体积抑制率分别为68.19%～76.79%和88.8%～91.87%,肿瘤生长受到明显抑制,与各对照组间比较差异均具有显著性(P＜0.05)。大体观察热疗组肿瘤区域可见明显的凝固性坏死,与周围组织分界清楚,磁流体满布于瘤内,MFH1组可见局灶的结节状或环形新鲜肿瘤组织残存,MFH2几乎全部坏死,呈豆腐渣样或液化。显微镜下对照组肿瘤细胞密集,生长活跃,可见散在小坏死灶,MF组瘤内磁流体呈团状分布,热疗组肿瘤大片坏死呈嗜红染的颗粒状或无结构组织,部分肿瘤细胞碎裂、核固缩,磁流体呈放射状弥漫分散于瘤内,可见摄取磁流体的肿瘤细胞及淋巴细胞浸润,坏死组织周围形成厚的纤维组织包裹,MFH1组尚可见局灶性或周围环形的活肿瘤细胞残存,MFH2组肿瘤组织几乎完全坏死,甚少见活肿瘤细胞残存。
结论:Fe_3O_4纳米磁流体在体内外均具有良好的升温性能,在体内可使肿瘤区成功的获得较均匀分布的50℃热消融温度,而正常组织不升温。磁流体对细胞无明显毒性;50℃的MFH可导致肿瘤组织明显坏死,显著抑制肿瘤生长;同时,热疗可促进瘤内磁流体的分散,实现热疗的旁效应;兔VX2瘤细胞可摄取磁性纳米粒子;磁热疗对肿瘤组织的杀伤作用与热疗次数相关;CT可作为敏感地检测体内磁流体分布的手段。一次性注射磁流体后,磁流体介导的50℃热疗兔VX2肝癌安全、可行、有效,靶向性好,且可进行重复热疗,具有潜在的临床应用价值。
第三部分磁流体介导的50℃局部热疗兔VX2肝癌的超声造影评价和对血管作用的研究
目的:探讨超声造影对磁流体热疗兔VX2肝癌的疗效评估价值,探讨磁流体热疗对兔VX2肝癌营养血管及对血管生成因子VEGF表达的影响。
方法:将接种14天的荷瘤兔随机分为5组及PT组、NS组、MF组、MFH1组、MFH2组,分组处理后于种植后4周行超声造影检查,观察肿瘤内血供情况及测量肿瘤坏死率,并与病理学检查相比较,同时进行血管壁弹力纤维染色及VEGF的免疫组化检测。
结果:各组超声造影测得的肿瘤坏死了率分别为17.89±7.45%、20.52±6.58%、16.78±8.92%、72.93±10.45%、94.28±3.54%。热疗组的坏死率明显高于各对照组,MFH1组可见局灶的结节状或环形强化,与肉眼及病理观察的肿瘤存活区一致,MFH2组几乎完全坏死,未见残存的活肿瘤组织,超声造影与病理测得的肿瘤坏死率比较无显著性差异,具有很好的一致性。磁热疗可使肿瘤滋养血管的血管壁破坏,弹力纤维断裂、散乱,血管管径越小效果越好,管径小于50μm的效果最好,MFH2组对血管的破坏程度明显大于MFH1组。种瘤后4周各组肿瘤VEGF的表达阳性率分别为63.87±7.24%、59.44±8.89%、65.25±10.04%、28.57±5.66%、5.84±2.97%,热疗组明显低于各对照组,差异具有显著性(P＜0.01),以MFH2组更低。
结论:超声造影可准确的反映磁流体热疗引起兔VX2肝癌凝固性坏死的范围及活肿瘤组织的残存,可作为评价磁流体热疗疗效的有效手段。磁流体介导的50℃热消融可有效的破坏肿瘤滋养血管,抑制VEGF的表达,可能是其治疗肿瘤的重要机制之一。
PartⅠEstablishment and sonographic evaluation of rabbit model bearing VX2 liver tumor
Objectives:To establish rabbit model bearing VX2 liver tumor. To analyze and compare its different sonographic features with color Dopple,power Doppler and contrast ultrasonography.
Methods:Twenty Japanese white rabbits were implanted into the left liver lobe with fresh VX2 tumor tissues for establishment of rabbit liver models.Two and four weeks after tumor implantation,tumor diameter was monitored by ultrasound and blood flow signals were detected by color Doppler,power Doppler and contrast ultrasound respectively,and then they were compared with each other.Ten rabbits were sacrificed randomly after sonogaphy and tumor diameter was measured and compared with the results of sonography.The phathologic features of VX2 tumor were observed by HE staining.
Results:All rabbits were successfully implanted with VX2 tumor. Tumor size was similar with the same growth time,and there was no significant difference between each other(P＞0.05.The maximum tumor diameters measured by ultrasound and caliper rule respectively had no significant difference(P＞0.05) In tumors,blood flow was detected sensitively by both color Doppler and power Doppler.Small liver tumors growing for two weeks were majorly charicterised by peripheral blood flow,which were dectected more by power Doppler than that by color Doppler.Blood flow of relatively large tumors growing for four weeks, was featured by peripheral large blood vessels or diffuse spot and striped abundant blood flow signals detected by both color Doppler and power Doppler,the difference of which was not significant.More integrity branches and smaller microvessels in both small and comparatively large tumors were detected by contrast ultrasound.The nested distribution of VX2 tumor cells with multinuclear division was examined by HE staining.
Conclusions:The rabbit model bearing VX2 liver tumor can be duplicated by highly successful rate.Ultrasonography is useful in measuring tumor size and monitoring its change.Color Doppler ultrasound and power Doppler both can sensitively detect blood flow signals in tumors,but power Doppler is more sensitive to detecte slower blood flow,especially for small liver tumor.Distirbution of intratumoral microvessels and blood perfusion in both small and large liver tumors can detected sensitively by contrast enhanced ultrasongraphy.
PartⅡFeasibility of local magnetic fluid hyperthermia(MFH) on rabbit VX2 liver tumor model and the effect on tumor growth
Objectives:To assess the potential of nanometer magnetic fluid heated under alternating magnetic field in vivo and in vitro,and to evaluate the feasibility of local MFH on rabbit VX2 liver tumor model and investigate the effect of it on growth of hepatic tumor.
Methods:Nanometer magnetic fluid was tested by transmission electron microscope and heated under different magetic field strength in vitro.Fourteen days after tumor implantation,the rabbits bearing VX2 liver tumor were randomly divided into five groups,including the pseudo-treatment(PT) control group,normal saline(NS) contol group, magnetic fluid(MF) control group,magnetic fluid hyperthermiaⅠ(MFH1) group and magnetic fluid hyperthermiaⅡ(MFH2) group.The rabbits were given intratumoral direct injection of magnetic fluid and immediately exposed to an alternating magnetic field and subsequently heated at 50℃for 30mins for group MFH1,and repeated hyperthermia after five days for group MFH2.CT scanning was performed at 1 and 14 days repectively after injection of magnetic fluid.Blood routine and their function of liver and kidney were tested before hyperthermia,and at 5 and 14 days after the first hyperthermia respectively.All animals were sacrificed on the 28th day after tumor implantation.Tumor size was measured,volume and growth rates of tumors were calculated.The changes of tumors were observed macroscopically and microscopically.
Results:Particle diameter of magnetic fluid was uniformity about 10nm.Temperature of magnetic fluid in vitro placed under an alternating magnetic field rose rapidly.In vivo,the temperature of tumor core and rim both rose rapidly and reached the desired temperature about 50℃within the first 5 to 10mins,and then was maintained in a relatively constant range of 50℃±2℃for 30mins by manually adjusting the magnetic flied strength.The limited highter density imaging of intratumoral magnetic fluid deposits compared to the surrounding tissue was observed clearly by CT scanning.Four weeks after tumor implantation,the tumor maximal diameter was(4.25±0.68) cm.(4.70± 1.12) cm、(4.16±0.88) cm、(2.83±0.51) cm、(2.03±0.34) cm separately, and the tumor volume was(25.824±11.92) cm~3、(32.01±13.14) cm~3、(23.35±12.17) cm~3、(7.43±1.86) cm~3、(2.62±1.35) cm~3 respectively in group PT,NS,MF,MFH1 and MFH2.Tumor volume inhibition rate of group MFH1 and MFH2 compared to the three control groups was 68.19%～76.79%and 88.8%～91.87%respectively.The growth of tumors was suppressed in hyperthermia groups.The heated area was macroscopically observed obvious coagulation necrosis,which had clear boundary line with the surrounding tissues.Under the microscope,large necrotic area for group MFH1 and almost complete necrosis for group MFH2 were observed.The intratumoral distribution of magnetic nanoparticles,especially in area of necrosis,appeared much more homogenous than the untreated.
Conclusions:The nanometer magntic fluid has good potential for temperature rising both in vitro and in vivo.The homogeneous high and relatively stable-state imtratumoral temperature of 50℃induced by magnetic fluid can be obtained successfully.Hyperthermia with magnetic fluid can suppress the growth of tumor and increase the tumor necrosis, and is safe and effective to treat rabbit VX2 liver tumor.CT can be served as a sensitive method to detect the distribution of intratumoral magnetic fluid.
PartⅢStudy on contrast ultrasonagraphic assessment of MFH in rabbit VX2 liver tumor model and the effect on tumor vessels
Objectives:To explore the reliability of contrast enhanced ultrasonography in assessing the reponse of rabbit VX2 liver tumors after MFH compared with histopathology,and to investigate the effect of MFH on tumor vessels.
Methods:Fourteen days after tumor implantaion,the rabbits bearing VX2 liver tumor were randomly divided into five groups, including group PT,NS,MF,MFH1 and MFH2.Two weeks later,tumor necrotic rate and blood flow were observed by sonography,and then all animals were sacrificed.Necrotic rate of tumors was assessed by HE staining and compared with the results of sonography;Elasticity fibre of vessel wall with Victoria blue and ponceau S histochemical staining was performed;Expression of VEGF of tumors was examined by immunohistochemistry.
Results:The tumor necrotic rate determined by sonogrsphy was 17.89±7.45%、20.52±6.58%、16.78±8.92%、72.93±10.45%、94.28±3.54 %respectively for group PT,NS,MF,MFH1 and MFH2,which had no significant difference compared with the results of phathologic examination.After MFH,vascular elasticity fibrin disrupted and vascular wall was destructed.Expression of VEGF decreased after MFH.The positive rate of VEGF in group MFH1 and MFH2 was 28.57±5.66%、5.84±2.97%respectively,significantly lower than that in each control group.
Conclusions:Contrast sonography can accurately discriminate the coagulation necrosis from residual tumors after MFH.MFH at 50℃can effectively injury tumor vessels and inhibit the positive expression of VEGF,which may play an important role in treatment of tumor.
目的:建立兔VX2肝癌模型,探讨该模型的超声影像学表现并进行比较评价,为该模型的应用提供实验依据。
方法:开腹直视下穿刺法将VX2瘤组织块种植于20只日本大耳白兔肝左叶,建立兔肝癌模型。分别于接种后2周、4周行彩色多普勒、能量多普勒及超声造影检查,半定量分级法分别比较三种超声对肿瘤血流检测率的敏感性,每次超声检查后随机处死10只荷瘤兔,测量肿瘤的实际大小取标本进行病理学鉴定,并与超声结果进行对照。
结果:兔肝癌种植成功率为100%,且该法建立的兔VX2肿瘤大小较一致,同期间比较无显著性差异(P＞0.05)。超声与实际测得肿瘤的最大径比较差异无显著性(P＞0.05),两者具有很好的一致性。彩色多普勒、能量多普勒及超声造影均能敏感的检出肿瘤内血流信号,种植2周的小肿瘤以瘤周供血为主,能量多普勒对血流的检出率明显高于彩色多普勒,而种植4周的较大肿瘤血管丰富,表现为瘤周粗大的供瘤血管或散在弥漫分布的点、条状血流,以高速低阻血流为主,彩色多普勒和能量多普勒均显示以三级病灶为主,无显著性差异,种植2周和4周的肿瘤超声造影显示“快进快出”的增强模式,可见完整、细致的肿瘤血管分支及其微小血管。VX2瘤细胞呈团片状或巢状浸润性分布,可见多个核分裂相,与肝实质无明显边界。
结论:瘤组织块穿刺种植法建立的兔VX2肝癌模型复制成功率高且稳定,实验可比性好。超声能有效的监测肿瘤大小及其变化。彩色多普勒和能量多普勒能敏感的检测出肿瘤血流,但能量多普勒对低速血流敏感,尤其是对小肝癌,而超声造影可更有效的反映大小肝癌瘤内微血管分布及血流灌注情况。
第二部分磁流体介导的50℃局部热疗兔VX2肝癌的可行性研究和对肿瘤生长的影响
目的:评估Fe_3O_4纳米磁流体的体内外升温性能,初步评价磁流体局部热疗兔VX2肝癌模型的可行性及其对肿瘤生长的影响。
方法:将纳米磁流体进行透射电镜检测和体外不同电流强度下的升温实验。将接种14天的荷瘤兔随机分为5组:即假治疗对照组(PT组)、生理盐水对照组(NS组)、磁流体对照组(MF组)、磁流体热疗Ⅰ组(MFH1组)、磁流体热疗Ⅱ组(MFH2组)。MFH1组在直接瘤内注射磁流体后立即暴露于交变磁场,50℃加热30min,MFH2组在5天后再重复加热一次。注射磁流体后第1天和第14天进行CT扫描。所有荷瘤兔分别于第一次热疗前和第一次热疗后5天、14天取血检查血常规及肝肾功能。种植后3周热疗组各处死2只实验兔病理学检查,4周后处死所有实验兔,测量肿瘤大小,计算肿瘤的体积抑制率,大体观察标本并进行病理学检查。
结果:磁流体粒径分布尚均匀,10nm左右,有部分聚集。体外磁流体升温速率随电流增大而增大,在电流为100A即磁场强度为47.95Gs时,磁流体先快速上升至70℃后变缓慢最后维持在80℃不上升。磁流体体内可在5～10min内升至50℃,通过手动调节磁场强度可将肿瘤温度控制在相对稳定的范围内50℃±2℃,而正常肝组织和直肠几乎不升温。CT可清晰地显示体内磁流体局限性的高密度影。热疗前后各组间同时间点及同组间不同时间点的血常规、肝肾功能比较均无明显差异(P＞0.05)。种植后4周各组肿瘤最大径分别(4.25±0.68)cm、(4.70±1.12)cm、(4.16±0.88)cm、(2.83±0.51)cm、(2.03±0.34)cm,肿瘤体积分别为(25.82±11.92)cm~3、(32.01±13.14)cm~3、(23.35±12.17)cm~3、(7.43±1.86)cm~3、(2.62±1.35)cm~3。MFH1组和MFH2组的肿瘤体积抑制率分别为68.19%～76.79%和88.8%～91.87%,肿瘤生长受到明显抑制,与各对照组间比较差异均具有显著性(P＜0.05)。大体观察热疗组肿瘤区域可见明显的凝固性坏死,与周围组织分界清楚,磁流体满布于瘤内,MFH1组可见局灶的结节状或环形新鲜肿瘤组织残存,MFH2几乎全部坏死,呈豆腐渣样或液化。显微镜下对照组肿瘤细胞密集,生长活跃,可见散在小坏死灶,MF组瘤内磁流体呈团状分布,热疗组肿瘤大片坏死呈嗜红染的颗粒状或无结构组织,部分肿瘤细胞碎裂、核固缩,磁流体呈放射状弥漫分散于瘤内,可见摄取磁流体的肿瘤细胞及淋巴细胞浸润,坏死组织周围形成厚的纤维组织包裹,MFH1组尚可见局灶性或周围环形的活肿瘤细胞残存,MFH2组肿瘤组织几乎完全坏死,甚少见活肿瘤细胞残存。
结论:Fe_3O_4纳米磁流体在体内外均具有良好的升温性能,在体内可使肿瘤区成功的获得较均匀分布的50℃热消融温度,而正常组织不升温。磁流体对细胞无明显毒性;50℃的MFH可导致肿瘤组织明显坏死,显著抑制肿瘤生长;同时,热疗可促进瘤内磁流体的分散,实现热疗的旁效应;兔VX2瘤细胞可摄取磁性纳米粒子;磁热疗对肿瘤组织的杀伤作用与热疗次数相关;CT可作为敏感地检测体内磁流体分布的手段。一次性注射磁流体后,磁流体介导的50℃热疗兔VX2肝癌安全、可行、有效,靶向性好,且可进行重复热疗,具有潜在的临床应用价值。
第三部分磁流体介导的50℃局部热疗兔VX2肝癌的超声造影评价和对血管作用的研究
目的:探讨超声造影对磁流体热疗兔VX2肝癌的疗效评估价值,探讨磁流体热疗对兔VX2肝癌营养血管及对血管生成因子VEGF表达的影响。
方法:将接种14天的荷瘤兔随机分为5组及PT组、NS组、MF组、MFH1组、MFH2组,分组处理后于种植后4周行超声造影检查,观察肿瘤内血供情况及测量肿瘤坏死率,并与病理学检查相比较,同时进行血管壁弹力纤维染色及VEGF的免疫组化检测。
结果:各组超声造影测得的肿瘤坏死了率分别为17.89±7.45%、20.52±6.58%、16.78±8.92%、72.93±10.45%、94.28±3.54%。热疗组的坏死率明显高于各对照组,MFH1组可见局灶的结节状或环形强化,与肉眼及病理观察的肿瘤存活区一致,MFH2组几乎完全坏死,未见残存的活肿瘤组织,超声造影与病理测得的肿瘤坏死率比较无显著性差异,具有很好的一致性。磁热疗可使肿瘤滋养血管的血管壁破坏,弹力纤维断裂、散乱,血管管径越小效果越好,管径小于50μm的效果最好,MFH2组对血管的破坏程度明显大于MFH1组。种瘤后4周各组肿瘤VEGF的表达阳性率分别为63.87±7.24%、59.44±8.89%、65.25±10.04%、28.57±5.66%、5.84±2.97%,热疗组明显低于各对照组,差异具有显著性(P＜0.01),以MFH2组更低。
结论:超声造影可准确的反映磁流体热疗引起兔VX2肝癌凝固性坏死的范围及活肿瘤组织的残存,可作为评价磁流体热疗疗效的有效手段。磁流体介导的50℃热消融可有效的破坏肿瘤滋养血管,抑制VEGF的表达,可能是其治疗肿瘤的重要机制之一。
PartⅠEstablishment and sonographic evaluation of rabbit model bearing VX2 liver tumor
Objectives:To establish rabbit model bearing VX2 liver tumor. To analyze and compare its different sonographic features with color Dopple,power Doppler and contrast ultrasonography.
Methods:Twenty Japanese white rabbits were implanted into the left liver lobe with fresh VX2 tumor tissues for establishment of rabbit liver models.Two and four weeks after tumor implantation,tumor diameter was monitored by ultrasound and blood flow signals were detected by color Doppler,power Doppler and contrast ultrasound respectively,and then they were compared with each other.Ten rabbits were sacrificed randomly after sonogaphy and tumor diameter was measured and compared with the results of sonography.The phathologic features of VX2 tumor were observed by HE staining.
Results:All rabbits were successfully implanted with VX2 tumor. Tumor size was similar with the same growth time,and there was no significant difference between each other(P＞0.05.The maximum tumor diameters measured by ultrasound and caliper rule respectively had no significant difference(P＞0.05) In tumors,blood flow was detected sensitively by both color Doppler and power Doppler.Small liver tumors growing for two weeks were majorly charicterised by peripheral blood flow,which were dectected more by power Doppler than that by color Doppler.Blood flow of relatively large tumors growing for four weeks, was featured by peripheral large blood vessels or diffuse spot and striped abundant blood flow signals detected by both color Doppler and power Doppler,the difference of which was not significant.More integrity branches and smaller microvessels in both small and comparatively large tumors were detected by contrast ultrasound.The nested distribution of VX2 tumor cells with multinuclear division was examined by HE staining.
Conclusions:The rabbit model bearing VX2 liver tumor can be duplicated by highly successful rate.Ultrasonography is useful in measuring tumor size and monitoring its change.Color Doppler ultrasound and power Doppler both can sensitively detect blood flow signals in tumors,but power Doppler is more sensitive to detecte slower blood flow,especially for small liver tumor.Distirbution of intratumoral microvessels and blood perfusion in both small and large liver tumors can detected sensitively by contrast enhanced ultrasongraphy.
PartⅡFeasibility of local magnetic fluid hyperthermia(MFH) on rabbit VX2 liver tumor model and the effect on tumor growth
Objectives:To assess the potential of nanometer magnetic fluid heated under alternating magnetic field in vivo and in vitro,and to evaluate the feasibility of local MFH on rabbit VX2 liver tumor model and investigate the effect of it on growth of hepatic tumor.
Methods:Nanometer magnetic fluid was tested by transmission electron microscope and heated under different magetic field strength in vitro.Fourteen days after tumor implantation,the rabbits bearing VX2 liver tumor were randomly divided into five groups,including the pseudo-treatment(PT) control group,normal saline(NS) contol group, magnetic fluid(MF) control group,magnetic fluid hyperthermiaⅠ(MFH1) group and magnetic fluid hyperthermiaⅡ(MFH2) group.The rabbits were given intratumoral direct injection of magnetic fluid and immediately exposed to an alternating magnetic field and subsequently heated at 50℃for 30mins for group MFH1,and repeated hyperthermia after five days for group MFH2.CT scanning was performed at 1 and 14 days repectively after injection of magnetic fluid.Blood routine and their function of liver and kidney were tested before hyperthermia,and at 5 and 14 days after the first hyperthermia respectively.All animals were sacrificed on the 28th day after tumor implantation.Tumor size was measured,volume and growth rates of tumors were calculated.The changes of tumors were observed macroscopically and microscopically.
Results:Particle diameter of magnetic fluid was uniformity about 10nm.Temperature of magnetic fluid in vitro placed under an alternating magnetic field rose rapidly.In vivo,the temperature of tumor core and rim both rose rapidly and reached the desired temperature about 50℃within the first 5 to 10mins,and then was maintained in a relatively constant range of 50℃±2℃for 30mins by manually adjusting the magnetic flied strength.The limited highter density imaging of intratumoral magnetic fluid deposits compared to the surrounding tissue was observed clearly by CT scanning.Four weeks after tumor implantation,the tumor maximal diameter was(4.25±0.68) cm.(4.70± 1.12) cm、(4.16±0.88) cm、(2.83±0.51) cm、(2.03±0.34) cm separately, and the tumor volume was(25.824±11.92) cm~3、(32.01±13.14) cm~3、(23.35±12.17) cm~3、(7.43±1.86) cm~3、(2.62±1.35) cm~3 respectively in group PT,NS,MF,MFH1 and MFH2.Tumor volume inhibition rate of group MFH1 and MFH2 compared to the three control groups was 68.19%～76.79%and 88.8%～91.87%respectively.The growth of tumors was suppressed in hyperthermia groups.The heated area was macroscopically observed obvious coagulation necrosis,which had clear boundary line with the surrounding tissues.Under the microscope,large necrotic area for group MFH1 and almost complete necrosis for group MFH2 were observed.The intratumoral distribution of magnetic nanoparticles,especially in area of necrosis,appeared much more homogenous than the untreated.
Conclusions:The nanometer magntic fluid has good potential for temperature rising both in vitro and in vivo.The homogeneous high and relatively stable-state imtratumoral temperature of 50℃induced by magnetic fluid can be obtained successfully.Hyperthermia with magnetic fluid can suppress the growth of tumor and increase the tumor necrosis, and is safe and effective to treat rabbit VX2 liver tumor.CT can be served as a sensitive method to detect the distribution of intratumoral magnetic fluid.
PartⅢStudy on contrast ultrasonagraphic assessment of MFH in rabbit VX2 liver tumor model and the effect on tumor vessels
Objectives:To explore the reliability of contrast enhanced ultrasonography in assessing the reponse of rabbit VX2 liver tumors after MFH compared with histopathology,and to investigate the effect of MFH on tumor vessels.
Methods:Fourteen days after tumor implantaion,the rabbits bearing VX2 liver tumor were randomly divided into five groups, including group PT,NS,MF,MFH1 and MFH2.Two weeks later,tumor necrotic rate and blood flow were observed by sonography,and then all animals were sacrificed.Necrotic rate of tumors was assessed by HE staining and compared with the results of sonography;Elasticity fibre of vessel wall with Victoria blue and ponceau S histochemical staining was performed;Expression of VEGF of tumors was examined by immunohistochemistry.
Results:The tumor necrotic rate determined by sonogrsphy was 17.89±7.45%、20.52±6.58%、16.78±8.92%、72.93±10.45%、94.28±3.54 %respectively for group PT,NS,MF,MFH1 and MFH2,which had no significant difference compared with the results of phathologic examination.After MFH,vascular elasticity fibrin disrupted and vascular wall was destructed.Expression of VEGF decreased after MFH.The positive rate of VEGF in group MFH1 and MFH2 was 28.57±5.66%、5.84±2.97%respectively,significantly lower than that in each control group.
Conclusions:Contrast sonography can accurately discriminate the coagulation necrosis from residual tumors after MFH.MFH at 50℃can effectively injury tumor vessels and inhibit the positive expression of VEGF,which may play an important role in treatment of tumor.
引文
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