靶向前列腺癌胃泌素释放肽受体^(68)Ga-DOTA-PEG4-BBN PET显像研究  

Gastrin-releasing peptide receptor targeted PET imaging of ^(68)Ga-DOTA-PEG4-BBN for prostate cancer

作　　者：袁佳琪 李迓曦 刘杜娟 任冉 李梦璐 冯宁翰 倪建明 Yuan Jiaqi;Li Yaxi;Liu Dujuan;Ren Ran;Li Menglu;Feng Ninghan;Ni Jianming(Department of Radiology,Affiliated Wuxi No.2 People′s Hospital,Nanjing Medical University,Wuxi 214002,China;Department of Nuclear Medicine,Jiangnan University Medical Center(JUMC),Wuxi 214002,China;Department of Urology,Affiliated Wuxi Clinical College of Nantong University,Nantong 226007,China)

机构地区：[1]南京医科大学附属无锡第二医院影像科,无锡214002 [2]江南大学附属中心医院核医学科,无锡214002 [3]南通大学附属无锡临床学院泌尿外科,南通226007

出　　处：《中华核医学与分子影像杂志》2024年第5期303-308,共6页Chinese Journal of Nuclear Medicine and Molecular Imaging

基　　金：无锡市卫生健康委员会科研项目(Z202209);无锡市"太湖人才计划"医疗卫生高层次人才(2020);上海市分子影像学重点实验室建设项目(18DZ2260400)。

摘　　要：目的设计和开发一种^(68)Ga标记的蛙皮素(BBN)类似物分子影像探针^(68)Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)-聚乙二醇(PEG)4-BBN,研究其靶向胃泌素释放肽受体(GRPR)高表达前列腺癌及在胰腺组织中低摄取的能力。方法基于BBN多肽的氨基酸序列,设计合成前体DOTA-PEG4-BBN,并在^(68)Ga标记后进行质量控制。选取GRPR高表达的前列腺癌PC3荷瘤裸鼠模型和GRPR低表达的结直肠癌HT29荷瘤裸鼠模型各3只,通过microPET/CT显像对比观察^(68)Ga-DOTA-PEG4-BBN的肿瘤摄取情况。选取PC3荷瘤裸鼠模型6只,其中3只模型鼠使用胃泌素释放肽阻断1 h,通过microPET/CT显像对比观察^(68)Ga-DOTA-PEG4-BBN的肿瘤摄取情况。显像后,对未阻断组3只PC3荷瘤裸鼠模型的离体组织进行放射性计数,测定^(68)Ga-DOTA-PEG4-BBN生物分布情况,以每克组织百分注射剂量率(%ID/g)表示。采用两独立样本t检验分析数据。结果^(68)Ga-DOTA-PEG4-BBN合成时间40 min,放射化学产率为50%~60%(未衰变校正),放化纯>95%;血清37℃温育4 h,其放化纯仍>95%。MicroPET/CT显像结果表明,PC3肿瘤部位的摄取是GRPR阻断后肿瘤部位的3.2倍[(1.34±0.24)与(0.42±0.03)%ID/g;t=5.47,P=0.005]。未阻断组PC3荷瘤裸鼠模型生物分布显示,^(68)Ga-DOTA-PEG4-BBN注射后1 h显像,15 min后胰腺的摄取[(0.150±0.058)%ID/g]明显低于肾脏、肺、肝脏的摄取[(9.452±0.234)、(0.720±0.041)、(1.572±0.213)%ID/g;t值:11.28~53.02,均P<0.001],探针对GRPR高表达荷瘤裸鼠模型的肿瘤/胰腺摄取比值可达16.92。结论新型探针^(68)Ga-DOTA-PEG4-BBN不仅能够特异性识别GRPR高表达肿瘤,还在胰腺组织中呈现低摄取,展现出其在前列腺癌分子影像诊断领域潜在的应用价值。Objective To design and develop a molecular imaging probe of^(68)Ga-labeled bombesin(BBN)analogue,^(68)Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(DOTA)-polyethylene glycol(PEG)4-BBN,and investigate its potential to target prostate cancer with high expression of gastrin-releasing peptide receptor(GRPR)while minimizing uptake in pancreatic tissue.Methods Based on the amino acid sequence of BBN peptides,the precursor DOTA-PEG4-BBN was designed and prepared,followed by labeling with^(68)Ga and conducting to quality control analysis.The tumor uptake of^(68)Ga-DOTA-PEG4-BBN was assessed by microPET/CT imaging on tumor-bearing nude mice models with PC3 of high GRPR expression or HT29 of low GRPR expression(3 mice per group).^(68)Ga-DOTA-PEG4-BBN microPET/CT imaging was also performed on 6 tumor-bearing nude mice models with PC3,among which 3 mice were treated with gastrin-releasing peptide antagonist 1 h prior to injection of the tracer(blocked group).After imaging,the ex vivo tissues of 3 PC3 tumor-bearing nude mice of the non-blocked group were examined for radioactivity counting to evaluation the biodistribution of^(68)Ga-DOTA-PEG4-BBN,and the percentage injected dose per gram of tissue(%ID/g)was calculated.Independent-sample t test was used for data analysis.Results The synthesis of^(68)Ga-DOTA-PEG4-BBN took 40 min,with the radiochemical yield of 50%-60%(no decay correction)and the radiochemical purity of over 95%.After incubation in the serum at 37℃for 4 h,the radiochemical purity remained more than 95%.The microPET/CT imaging results indicated that the uptake in the PC3 tumor was 3.2 times higher than the uptake in the tumor after GRPR blockade((1.34±0.24)vs(0.42±0.03)%ID/g;t=5.47,P=0.005).After the injection of^(68)Ga-DOTA-PEG4-BBN at 1 h and following imaging for 15 min,the PC3 tumor-bearing nude mice models of the non-blocked group showed that the pancreatic uptake((0.150±0.058)%ID/g)was significantly lower than that in kidneys,lungs and liver((9.452±0.234),(0.720±0.041),(1.572±0.213)%I

关 键 词：前列腺肿瘤 受体 铃蟾肽 同位素标记 镓放射性同位素 正电子发射断层显像术 小鼠 裸 

分 类 号：R737.25[医药卫生—肿瘤] R816.7[医药卫生—临床医学]