MRI对比剂Gd-DO3A-Ether-Rhein的合成及其坏死亲和性研究  

Synthesis and evaluation of necrosis avidity of MRI contrast agent Gd-DO3A-Ether-Rhein

作　　者：张立邦 张东建[2,3] 高萌 金乔梅[2,3] 吴天泽 杨阳[2,3] 张健 殷志琦 ZHANG Libang;ZHANG Dongjian;GAO Meng;JIN Qiaomei;WU Tianze;YANG Yang;ZHANG Jian;YIN Zhiqi(Department of TCMs Pharmaceuticals,School of TCM&State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009;Laboratory of Translational Medicine,Jiangsu Provincial Academy of Traditional Chinese Medicine,Nanjing 210028;Affiliated Hospital of Integrated Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210028,China)

机构地区：[1]中国药科大学中药学院中药制剂系&天然药物活性组分与药效国家重点实验室,南京210009 [2]江苏省中医药研究院转化医学实验室,南京210028 [3]南京中医药大学附属中西医结合医院,南京210028

出　　处：《中国药科大学学报》2019年第4期444-451,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81771870);江苏省“六大人才高峰”高层次人才项目(YY-011);江苏省自然科学基金资助项目(No.20171512);高层次卫生人才“六个一工程”拔尖人才科研资助项目(No.LGY2018075);双一流学科创新团队资助项目(No.CPU2018GF05,No.CPU2018GY31)~~

摘　　要：以大黄酸为底物、醚链为连接臂合成磁共振成像(MRI)对比剂并评价其坏死亲和性。合成新的配体10-{[6-(1,8-二羟基蒽醌-3-甲酰氨基)乙氧基乙基]氨基}羰酰甲基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸(DO3A-Ether-Rhein,即E1),再与Gd 3+配位得到顺磁性对比剂10-{[6-(1,8-二羟基蒽醌-3-甲酰氨基)乙氧基乙基]氨基}羰酰甲基-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸合钆(Gd-DO3A-Ether-Rhein,即GdE1)。分别在高热诱导的人肝癌HepG2细胞坏死模型和微波消融诱导的大鼠肌肉坏死模型上评价探针的坏死亲和性。动物试验中,分别在给予GdE1(0.1 mmol/kg)前和给药后0~9 h进行MRI成像,Gd-DOTA(1,4,7,10-四乙酸-1,4,7,10-四氮杂环十二烷合钆)作为对照。MRI成像结果表明,坏死细胞的信号强度(4 369±70)显著高于正常细胞(2 555±84)(P<0.05);在GdE1给药后3 h,坏死肌肉与正常肌肉的对比度为2.00±0.12,显著高于给药后0 h(1.27±0.03)(P<0.05)。上述结果表明,GdE1具有良好的坏死亲和性,在坏死相关疾病的诊断上显示出良好的应用潜力。The aim of this study was to synthesize and evaluate the necrosis avidity of MRI contrast agent based on rhein and linked by ether.The novel ligand 10-{[6-(1,8-dihydroxyanthraquinone-3-carboxamido)ethoxyethyl]amino}carbonylmethyl-1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid(DO3A-Ether-Rhein,E1)was synthesized by two steps of acylation and deprotection reaction.The paramagnetic gadolinium 10-{[6-(1,8-dihydroxyanthraquinone-3-carboxamido)ethoxyethyl]amino}carbonylmethyl-1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid(Gd-DO3A-Ether-Rhein,GdE1)was obtained by coordination of Gd 3+with the above ligand.We examined the necrotic avidity of GdE1 in human hepatocellular carcinoma HepG2 cell necrosis induced by hyperthermia in vitro and in rat model with muscular necrosis induced by microwave ablation in vivo by MRI.The MRI was implemented before administration of GdE1 and during 0-9 h after administration of GdE1(0.1 mmol/kg),and Gd-DOTA(gadolinium 1,4,7,10-tetraacetic acid-1,4,7,10-tetraazacyclo dodecane)was used as control.The signal intensity of necrotic cells(4 369±70)was significantly higher than that of normal cells(2 555±84)(P<0.05).Similarly,the contrast ratio between necrotic and normal muscle at 3 h after administration of GdE1(2.00±0.12)was remarkblely higher than that at 0 h after administration of GdE1(1.27±0.03)(P<0.05).Therefore,GdE1 presents good necrosis affinity and has the potential to be used in the diagnosis of necrosis-related diseases.

关 键 词：大黄酸 Gd-DO3A-Ether-Rhein 坏死亲和性 对比剂 磁共振成像 

分 类 号：R445.2[医药卫生—影像医学与核医学] R914.5[医药卫生—诊断学]