~(11)C-甲异靛PET用于肺癌诊断和化疗疗效监测的实验
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摘要
目的:1、研究~(11)C-甲异靛在体外四种不同肺癌细胞中的摄取情况;2、研究~(11)C-甲异靛在荷瘤小鼠(LA795肺癌)模型体内生物分布与PET显像;3、研究~(11)C-甲异靛在炎症小鼠(松节油急性炎症)模型体内生物分布与PET显像;4、评价~(11)C-甲异靛作为一种新的PET示踪剂在荷瘤小鼠模型化疗疗效监测中的价值。
方法:1、在LA795、95-C、95-D及H460等4种不同肺癌细胞中分别加入合成的~(11)C-甲异靛(实验组)或~(18)F-FDG(对照组),根据2种示踪剂半衰期的不同,实验组细胞分别于5、15、20分钟取出并检测各肺癌细胞的放射性摄取活度,对照组细胞分别于30、60、90、120、150分钟取出并检测各肺癌细胞株的放射性摄取活度;2、20只荷瘤小鼠(LA795肺癌)被随机分为4组,其中A组、B组、C组为实验组,经尾静脉分别于注射~(11)C-甲异靛后5min、15min、20min进行PET显像并处死小鼠,取心、肝、肺、肾、脑、肌肉和肿瘤组织,用井型探测仪测量~(11)C-甲异靛在上述各脏器组织的生物分布,D组为对照组,给予注射~(18)F-FDG后60min进行PET显像和生物分布测定;3、10只炎症小鼠(松节油急性炎症)模型随机分为~(11)C-甲异靛实验组和~(18)F-FDG对照组。~(11)C-甲异靛组在注入~(11)C-甲异靛15分钟后PET显像并处死,取心、肝、肺、肾脑、肌肉和肿瘤组织,用井型探测仪测量~(11)C-甲异靛在体内的生物分布,~(18)F-FDG组在注入~(18)F-FDG后60分钟行PET显像、处死并检测其生物分布。4、30只荷瘤小鼠(LA795肺腺癌)随机分为A组(对照组)、B组(化疗1天组)和C组(化疗2天组),每组内再分为~(11)C-甲异靛组和~(18)F-FDG组两个亚组,化疗组小鼠经尾静脉分别注入~(11)C-甲异靛或~(18)F-FDG,~(11)C-甲异靛亚组在注入~(11)C-甲异靛15分钟后显像并处死,用井型探测仪测量~(11)C-甲异靛在小鼠肿瘤放射分布,~(18)F-FDG亚组在注入~(18)F-FDG后60min显像并处死,用井型探测仪测量~(18)F-FDG在小鼠肿瘤放射分布。应用免疫组化法测定肿瘤组织增殖细胞核抗原(PCNA)的表达水平。
结果:1、在体外四种肺癌细胞对~(11)C-甲异靛和~(18)F-FDG均有摄取,细胞对~(11)C-甲异靛的放射性摄取活度高于~(18)F-FDG。~(11)C-甲异靛的摄取高峰在注药15分钟时,其中以H460细胞摄取的放射活度最高;细胞对~(18)F-FDG的摄取随时间延长而持续增长,其增幅以90分钟时间点最高,其中以95D细胞摄取的放射活度增幅最高。比较四种肿瘤细胞在摄取2种不同示踪剂在放射活度增幅高峰时的摄取放射活度有明显统计学差异。2、~(11)C-甲异靛在荷瘤小鼠体内生物分布见肺癌组织有较高的放射性摄取,放射性主要分布在肾、肝等腹腔脏器,最高的为肝脏,其次为肾、肿瘤、心,在注药后15min肿瘤对血、肌肉及肺的T/NT均大于2,肿瘤PET显像清晰。3、炎症组织对~(11)C-甲异靛摄取值明显低于FDG,~(11)C-甲异靛组组放射性摄取最高的依次为肾、肝、心组织,炎症组织对血、肺及肌肉组织的放射性比值均小于2;而对~(18)F-FDG放射性摄取最高的依次为心、肾、炎症组织,炎症组织对血及肌肉组织的放射性比值大于2。两组炎症组织对血、肺、肌肉的放射性比值存在显著性差异。炎性组织仅在~(18)F-FDG PET中显像。4、~(11)C-甲异靛组荷瘤小鼠经顺铂1天化疗后(B组)和2天化疗后(C组)的肿瘤放射性摄取值分别为0.94、0.85,比未行化疗的对照组(A组)的放射性摄取值1.31有明显下降,肿瘤放射性摄取值B组、C组与A组比较统计学存在显著性差异。~(18)F-FDG组荷瘤小鼠B组和C组化疗后的肿瘤放射性摄取值,比A组降低,但无统计学显著性差异。PET显像见B组和C组(分别行化疗1、2天)的~(11)C-甲异靛亚组荷瘤小鼠的肿瘤部位放射性浓聚减低明显;而~(18)F-FDG亚组荷瘤小鼠的肿瘤部位放射性浓聚较A组无明显变化。PCNA免疫组化检查见三组肿瘤细胞均有表达,以A组表达最高,B组、C组依次下降,B组和C组PCNA值与A组相比较均存在显著性差异,各组内~(11)C-甲异靛亚组和~(18)F-FDG亚组无显著性差异。
结论: ~(11)C-甲异靛有较高的肿瘤特异性,可被肺癌细胞所摄取。在荷瘤小鼠模型中肺癌组织对~(11)C-甲异靛摄取高于正常组织,PET显像清楚,在炎性组织在~(11)C-甲异靛PET中未显像,提示可用于肺癌诊断及肺癌与炎症的鉴别诊断。肺癌化疗后~(11)C-甲异靛摄取较~(18)F-FDG明显降低,能反映肺癌细胞的增值状况,可用于对化疗的疗效进行监测。
Objective: 1. To investigate uptake of ~(11)C-meisoindigo by four kinds of lung cancer cells ( LA795, 95-C, 95-D and H460). 2. To investigate the biodistribution and positron emission tomography (PET) imaging of ~(11)C-meisoindigo in a murine model of LA795 lung carcinoma. 2. To study the biodistribution and PET imaging of ~(11)C-meisoindigo in a murine model of inflammation. 3. To evaluate the use of ~(11)C-meisoindigo as a new PET tracer for monitoring tumor response to chemotherapy.
Methods: 1. Four kinds of lung cancer cells were divided into ~(11)C-meisoindigo and ~(18)F-FDG groups, ~(11)C-meisoindigo or ~(18)F-FDG was added into different lung cancer cells respectively. According to the different tracers and after adding time, cell uptake of ~(11)C-meisoindigo group examined at 5、15、20min with well-gammadetector, cell uptake of ~(18)F-FDG groups examined at 30、60、90、120、150min. 2. 20 mice bearing LA795 lung adenocarcinoma were divided into four groups according to the different tracers and time after injection at random, A group(5min), B group(15min,) and C group(20min) after ~(11)C-meisoindigoinjection, D group( 60min ) after ~(11)F-FDG injection. The biodistribution of mice for ~(11)C-meisoindigo was measured with well-gamma detector at 5, 15 and 20min after ~(11)C-meisoindigo injection from tail veins. And the biodistribution of mice for F-FDG was examined at 60min after injection. In addition, the PET imaging of mice was performed using two tracers. 3. 10 the mice model with inflammation were divided into two groups according to the different tracers at random, ~(11)C-meisoindigo and ~(18)F-FDG group. The biodistribution of mice for ~(11)C-meisoindigo and ~(18)F-FDG was measured with well-gamma detector atl5, 60 min after injection, respectively. The PET imaging of mice was also performed using two tracers. 4. 30 mice bearing LA795 lung adenocarcinoma were divided into three groups according to days of chemotherapy at random, A group(untreated controls), B group(1 day) and C group(2 day )after chemotherapy. Each group was also divided into two groups according to two radioactive tracers, ~(11)C-meisoindigo and ~(18)F-FDG groups. The mice of group B and group C were treated with cisplatin, then, injected with ~(11)C-meisoindigo or ~(18)F-FDG. Tumor biodistribution of all mice was measured with well-gamma detector at 15, 60 min after injection and the PET imaging of mice was performed respectively. Tumor proliferation was determined by immunohistochemical examination of proliferating cell nuclear antigen (PCNA).
Results: 1. ~(11)C-meisoindigo and ~(18)F-FDG were all uptake by four kinds of lung cancer cells. uptake of ~(11)C-meisoindigo was more than ~(18)F-FDG, time of maximum uptake of ~(11)C-meisoindigo was 15min after injection, uptake of ~(11)C-meisoindigo by H460 cell was more than others. Uptake of ~(18)F-FDG by cells increased with time prolonged, The maximum increasing time of uptake was 90min, uptake of ~(18)F-FDG by 95D cell was more than others. 2. In the biodistribution study of ~(11)C-meisoindigo, considerable radioactive uptake of tumor was observed, and much radioactivity was showed in liver and kidney. The ratios of tumor/blood, tumor/muscle and tumor/lung were all above 2.0. The tumor PET images with ~(11)C-meisoindigo were clear. 3. Uptake of ~(18)F-FDG by inflammation tissues was higher than those of ~(11)C-meisoindigo. Inflammatory tissues were visible in ~(18)F-FDG PET images, no visible in ~(11)C-meisoindigo PET. 4. Tumor ~(11)C-meisoindigo uptake decreased rapidly after treatment of cisplatin. ~(11)C-meisoindigo uptake in tumor was significantly was decreased more than that of ~(18)F-FDG The PET imaging confirmed lower tumor ~(11)C-meisoindigo retention in group B and group C compared with group A. PCNA decreased after treatment of cisplatin in B and C groups than A group significantly.
Conclusions: Lung cancer cells can uptake of ~(11)C-meisoindigo, and the uptake of ~(11)C-meisoindigo in lung cancer tissues is higher than that normal tissues, and inflammatory tissues are invisible in ~(11)C-meisoindigo PET images, so the lung cancer could be identified with ~(11)C-meisoindigo PET imaging. The decrease in tumor ~(11)C-meisoindigo uptake after chemotherapy was more than that of ~(18)F-FDG Changes in ~(11)C-meisoindigo uptake could correspond changes of PCNA, ~(11)C-meisoindigo is a promising PET tracer for monitoring Chemotherapeutic effect of lung cancer. Our preliminary study of ~(11)C-meisoindigo in lung cancer showed it maybe a promising PET tracer in lung cancer diagnosis and chemotherapeutic effect monitoring
方法:1、在LA795、95-C、95-D及H460等4种不同肺癌细胞中分别加入合成的~(11)C-甲异靛(实验组)或~(18)F-FDG(对照组),根据2种示踪剂半衰期的不同,实验组细胞分别于5、15、20分钟取出并检测各肺癌细胞的放射性摄取活度,对照组细胞分别于30、60、90、120、150分钟取出并检测各肺癌细胞株的放射性摄取活度;2、20只荷瘤小鼠(LA795肺癌)被随机分为4组,其中A组、B组、C组为实验组,经尾静脉分别于注射~(11)C-甲异靛后5min、15min、20min进行PET显像并处死小鼠,取心、肝、肺、肾、脑、肌肉和肿瘤组织,用井型探测仪测量~(11)C-甲异靛在上述各脏器组织的生物分布,D组为对照组,给予注射~(18)F-FDG后60min进行PET显像和生物分布测定;3、10只炎症小鼠(松节油急性炎症)模型随机分为~(11)C-甲异靛实验组和~(18)F-FDG对照组。~(11)C-甲异靛组在注入~(11)C-甲异靛15分钟后PET显像并处死,取心、肝、肺、肾脑、肌肉和肿瘤组织,用井型探测仪测量~(11)C-甲异靛在体内的生物分布,~(18)F-FDG组在注入~(18)F-FDG后60分钟行PET显像、处死并检测其生物分布。4、30只荷瘤小鼠(LA795肺腺癌)随机分为A组(对照组)、B组(化疗1天组)和C组(化疗2天组),每组内再分为~(11)C-甲异靛组和~(18)F-FDG组两个亚组,化疗组小鼠经尾静脉分别注入~(11)C-甲异靛或~(18)F-FDG,~(11)C-甲异靛亚组在注入~(11)C-甲异靛15分钟后显像并处死,用井型探测仪测量~(11)C-甲异靛在小鼠肿瘤放射分布,~(18)F-FDG亚组在注入~(18)F-FDG后60min显像并处死,用井型探测仪测量~(18)F-FDG在小鼠肿瘤放射分布。应用免疫组化法测定肿瘤组织增殖细胞核抗原(PCNA)的表达水平。
结果:1、在体外四种肺癌细胞对~(11)C-甲异靛和~(18)F-FDG均有摄取,细胞对~(11)C-甲异靛的放射性摄取活度高于~(18)F-FDG。~(11)C-甲异靛的摄取高峰在注药15分钟时,其中以H460细胞摄取的放射活度最高;细胞对~(18)F-FDG的摄取随时间延长而持续增长,其增幅以90分钟时间点最高,其中以95D细胞摄取的放射活度增幅最高。比较四种肿瘤细胞在摄取2种不同示踪剂在放射活度增幅高峰时的摄取放射活度有明显统计学差异。2、~(11)C-甲异靛在荷瘤小鼠体内生物分布见肺癌组织有较高的放射性摄取,放射性主要分布在肾、肝等腹腔脏器,最高的为肝脏,其次为肾、肿瘤、心,在注药后15min肿瘤对血、肌肉及肺的T/NT均大于2,肿瘤PET显像清晰。3、炎症组织对~(11)C-甲异靛摄取值明显低于FDG,~(11)C-甲异靛组组放射性摄取最高的依次为肾、肝、心组织,炎症组织对血、肺及肌肉组织的放射性比值均小于2;而对~(18)F-FDG放射性摄取最高的依次为心、肾、炎症组织,炎症组织对血及肌肉组织的放射性比值大于2。两组炎症组织对血、肺、肌肉的放射性比值存在显著性差异。炎性组织仅在~(18)F-FDG PET中显像。4、~(11)C-甲异靛组荷瘤小鼠经顺铂1天化疗后(B组)和2天化疗后(C组)的肿瘤放射性摄取值分别为0.94、0.85,比未行化疗的对照组(A组)的放射性摄取值1.31有明显下降,肿瘤放射性摄取值B组、C组与A组比较统计学存在显著性差异。~(18)F-FDG组荷瘤小鼠B组和C组化疗后的肿瘤放射性摄取值,比A组降低,但无统计学显著性差异。PET显像见B组和C组(分别行化疗1、2天)的~(11)C-甲异靛亚组荷瘤小鼠的肿瘤部位放射性浓聚减低明显;而~(18)F-FDG亚组荷瘤小鼠的肿瘤部位放射性浓聚较A组无明显变化。PCNA免疫组化检查见三组肿瘤细胞均有表达,以A组表达最高,B组、C组依次下降,B组和C组PCNA值与A组相比较均存在显著性差异,各组内~(11)C-甲异靛亚组和~(18)F-FDG亚组无显著性差异。
结论: ~(11)C-甲异靛有较高的肿瘤特异性,可被肺癌细胞所摄取。在荷瘤小鼠模型中肺癌组织对~(11)C-甲异靛摄取高于正常组织,PET显像清楚,在炎性组织在~(11)C-甲异靛PET中未显像,提示可用于肺癌诊断及肺癌与炎症的鉴别诊断。肺癌化疗后~(11)C-甲异靛摄取较~(18)F-FDG明显降低,能反映肺癌细胞的增值状况,可用于对化疗的疗效进行监测。
Objective: 1. To investigate uptake of ~(11)C-meisoindigo by four kinds of lung cancer cells ( LA795, 95-C, 95-D and H460). 2. To investigate the biodistribution and positron emission tomography (PET) imaging of ~(11)C-meisoindigo in a murine model of LA795 lung carcinoma. 2. To study the biodistribution and PET imaging of ~(11)C-meisoindigo in a murine model of inflammation. 3. To evaluate the use of ~(11)C-meisoindigo as a new PET tracer for monitoring tumor response to chemotherapy.
Methods: 1. Four kinds of lung cancer cells were divided into ~(11)C-meisoindigo and ~(18)F-FDG groups, ~(11)C-meisoindigo or ~(18)F-FDG was added into different lung cancer cells respectively. According to the different tracers and after adding time, cell uptake of ~(11)C-meisoindigo group examined at 5、15、20min with well-gammadetector, cell uptake of ~(18)F-FDG groups examined at 30、60、90、120、150min. 2. 20 mice bearing LA795 lung adenocarcinoma were divided into four groups according to the different tracers and time after injection at random, A group(5min), B group(15min,) and C group(20min) after ~(11)C-meisoindigoinjection, D group( 60min ) after ~(11)F-FDG injection. The biodistribution of mice for ~(11)C-meisoindigo was measured with well-gamma detector at 5, 15 and 20min after ~(11)C-meisoindigo injection from tail veins. And the biodistribution of mice for F-FDG was examined at 60min after injection. In addition, the PET imaging of mice was performed using two tracers. 3. 10 the mice model with inflammation were divided into two groups according to the different tracers at random, ~(11)C-meisoindigo and ~(18)F-FDG group. The biodistribution of mice for ~(11)C-meisoindigo and ~(18)F-FDG was measured with well-gamma detector atl5, 60 min after injection, respectively. The PET imaging of mice was also performed using two tracers. 4. 30 mice bearing LA795 lung adenocarcinoma were divided into three groups according to days of chemotherapy at random, A group(untreated controls), B group(1 day) and C group(2 day )after chemotherapy. Each group was also divided into two groups according to two radioactive tracers, ~(11)C-meisoindigo and ~(18)F-FDG groups. The mice of group B and group C were treated with cisplatin, then, injected with ~(11)C-meisoindigo or ~(18)F-FDG. Tumor biodistribution of all mice was measured with well-gamma detector at 15, 60 min after injection and the PET imaging of mice was performed respectively. Tumor proliferation was determined by immunohistochemical examination of proliferating cell nuclear antigen (PCNA).
Results: 1. ~(11)C-meisoindigo and ~(18)F-FDG were all uptake by four kinds of lung cancer cells. uptake of ~(11)C-meisoindigo was more than ~(18)F-FDG, time of maximum uptake of ~(11)C-meisoindigo was 15min after injection, uptake of ~(11)C-meisoindigo by H460 cell was more than others. Uptake of ~(18)F-FDG by cells increased with time prolonged, The maximum increasing time of uptake was 90min, uptake of ~(18)F-FDG by 95D cell was more than others. 2. In the biodistribution study of ~(11)C-meisoindigo, considerable radioactive uptake of tumor was observed, and much radioactivity was showed in liver and kidney. The ratios of tumor/blood, tumor/muscle and tumor/lung were all above 2.0. The tumor PET images with ~(11)C-meisoindigo were clear. 3. Uptake of ~(18)F-FDG by inflammation tissues was higher than those of ~(11)C-meisoindigo. Inflammatory tissues were visible in ~(18)F-FDG PET images, no visible in ~(11)C-meisoindigo PET. 4. Tumor ~(11)C-meisoindigo uptake decreased rapidly after treatment of cisplatin. ~(11)C-meisoindigo uptake in tumor was significantly was decreased more than that of ~(18)F-FDG The PET imaging confirmed lower tumor ~(11)C-meisoindigo retention in group B and group C compared with group A. PCNA decreased after treatment of cisplatin in B and C groups than A group significantly.
Conclusions: Lung cancer cells can uptake of ~(11)C-meisoindigo, and the uptake of ~(11)C-meisoindigo in lung cancer tissues is higher than that normal tissues, and inflammatory tissues are invisible in ~(11)C-meisoindigo PET images, so the lung cancer could be identified with ~(11)C-meisoindigo PET imaging. The decrease in tumor ~(11)C-meisoindigo uptake after chemotherapy was more than that of ~(18)F-FDG Changes in ~(11)C-meisoindigo uptake could correspond changes of PCNA, ~(11)C-meisoindigo is a promising PET tracer for monitoring Chemotherapeutic effect of lung cancer. Our preliminary study of ~(11)C-meisoindigo in lung cancer showed it maybe a promising PET tracer in lung cancer diagnosis and chemotherapeutic effect monitoring
引文
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