^(99m)Tc-EDTA-MN的制备及其在荷瘤裸鼠显像中的初步评价  

Preparation of ^(99m)Tc-EDTA-MN and Its Bioimaging in Mouse

作　　者：齐永帅 李贵平[1] 池晓华[1] 杜丽[1] 黄凯[1] 张辉[1] 黄宝丹[1] 

机构地区：[1]南方医科大学南方医院核医学科,广州510515

出　　处：《中国肺癌杂志》2015年第7期422-426,共5页Chinese Journal of Lung Cancer

基　　金：广东省科技计划项目(No.2012B031800391);广东省自然科学基金项目(No.S2013010014420);南方医院院长基金项目(No.2012Z008)资助~~

摘　　要：背景与目的乏氧是实体肿瘤的一个重要生物学特征,组织乏氧导致肿瘤对放疗和化疗不敏感,从而增加其对放化疗的抵抗性,因此确定肿瘤组织乏氧程度具有重要意义。核医学乏氧显像能够反映肿瘤组织乏氧程度,他能选择性地滞留在乏氧细胞或组织中,主要包括硝基咪唑类和非硝基咪唑类;其中硝基咪唑类肿瘤乏氧细胞显像剂是国内外研究的较多并且具有发展前景的一类用于肿瘤治疗的药物。本研究应用放射性核素标记技术对研制具有临床应用价值的肿瘤乏氧显像剂乙二胺四乙酸-甲硝唑酯(ethylenediaminetetraacetic acid-metronidazole,EDTAMN)配体进行标记。探讨采用氯化亚锡还原法法进行99mTc标记的可行性,评价99mTc-EDTA-MN的放化特性,观察99mTc-EDTA-MN在非小细胞肺癌(non-small cell lung cancer,NSCLC)裸鼠模型体内的生物学分布特点,为其进一步研究与应用提供实验依据。方法采用氯化亚锡还原法进行EDTA-MN配体的99mTc标记,分别对反应量(10 mg、5 mg、2 mg)、氯化亚锡用量(8 mg/m L、4 mg/m L、2 mg/m L)、标记体系p H(2、4、5、6)逐一进行试验,采用正交试验设计进行分析,以寻找最佳标记条件。采用纸层析法和高效液相色谱法测定标记率、放化纯度、脂水分配系数及室温下在生理盐水的体外稳定性,并对标记物在裸鼠体内的生物学分布进行初步显像研究。结果最佳标记条件下的标记率(84.11±2.83)%,放射化学纯度大于90%,室温下放置12 h在生理盐水中较稳定。脂水分配系数为lg P=-3.05。尾静脉注射99mTc-EDTA-MN的3 h内,裸鼠肿瘤模型初步显像示0.5 h时膀胱区域见大量放射性浓聚,1 h时肿瘤显影清晰,其余脏器内放射性分布均较低。采用ROI技术测得0.5 h、1 h、2 h、3 h肿瘤部位单位面积内放射性计数(88.14±11.59)、(123.17±9.06)、(98.08±14.40)和(79.87±10.57),并计算肿瘤与肝脏区域的T/NT比值分别为(1.95±0.19)、(3Background and objective Hypoxia is an important biological characteristics of solid tumor, it is not sensitive to radiotherapy and chemotherapy for which is the presence of hypoxic cell, thus increasing their resistance to conventional radiotherapy and chemotherapy, therefore, the detection of hypoxia degree of tumor tissue is of great significance. The hypoxia imaging of nuclear medicine can reflect the degree of tissue hypoxia, which can selectively retained on the hypoxic cells or tissues, including nitroimidazole and non nitroimidazole; the nitroimidazole is widely and deeply researched as hypoxic celles developer in China and abroad at present. The research about application of radionuclide labelled technique has clinical application value to develop the hypoxia imaging agent EDTA-MN complexes which was labeled. To study the feasibility of 99mTc by direct labeling method, the radiochemical properties evaluation of 99mTc-EDTA-MN, and observe the distribution characteristics of 99mTc radiolabeled EDTA-MN in the xenograft lung cancer nude mice bearing non-small cell lung cancer cell （A549）, and provide experimental evidence for its further research and application. Methods The radiolabeling of EDTA-MN with 99mTc was performed with direct labeling method, respectively, on the reaction dosage （10 mg, 5 mg, 2 mg）, stannous chloride dosage （8 mg/mL, 4 mg/mL, 2 mg/mL）, mark system pH （2, 4, 5, 6） one by one test, using orthogonal design analysis, to find the optimal labeling conditions. Labelling rate, radiochemical purity, lipid-water partition coefficient and in vitro stability in normal saline （NS） were determined by TLC and HPLC, and the preliminary study on the distribution of 99mTc-EDTA-MN in nude mice. Results The labeling rate of 99mTc-EDTA-MN with the best labeling conditions was （84.11＋2.83）%, and the radiochemical purity was higher than 90% by HPLC purification, without any notable decomposition at room temperature over a period of 12 h. The partition coefficient was lgP=-3.05,

关 键 词：肺肿瘤 乏氧显像剂 乙二胺四乙酸-甲硝唑酯 放化纯度 

分 类 号：R734.2[医药卫生—肿瘤]