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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 1  |  Page : 112-120

Preclinical evaluation of [ 111 In]-DOTA-trastuzumab for clinical trials


Radiopharmacy Research Group, Radiation Application Research School, Nuclear Science and Technology Research Institute, 11365-3486, Tehran, Iran

Correspondence Address:
Amir Reza Jalilian
Nuclear Science Research School, Nuclear Science and Technology Research Institute, 11365-3486, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.131434

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Context: Herceptin and its fragments have been radiolabeled and used in the imaging of human epidermal growth factor receptor 2 (HER2)/neu-positive tumors and development of diagnostic kits is of great importance in radiopharmacy. Aims: In this study, 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-trastuzumab ( 111 In-DOTA-trastuzumab) was successively prepared and evaluated for ultimate use in the HER2 antigen imaging in oncology. Settings and Design: The conjugate was prepared, labeled and evaluated using in vitro (radioimmunoassay [RIA], enzyme-linked immunosorbent assay (ELISA), stability, binding, internalization)/in vivo (bio-distribution, single-photon emission computed tomography [SPECT]) experiments. Materials and Methods: 111 In-DOTA-trastuzumab was prepared followed by determination of radiochemical purity (RCP), integrity of protein, immunoreactivity of radiolabeled antibody with HER2/neu antigen (by SkBr3 cell line binding and RIA methods) were determined followed by stability tests, internalization studies and the tissue bio-distribution determination in wild-type rats as well as SPECT imaging in SkBr3-bearing mice. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD) and the data were compared using Student's t-test. Statistical significance was defined as P < 0.05. Results: 111 In-DOTA-trastuzumab was prepared (RCP >95 ± 0.5%, S.A. 5.3 μCi/μg) with the average number of chelators per antibody of 6:1 showing significant immune-reactivity retention using ELISA. In vitro stability was >90% in phosphate buffered saline and 80 ± 0.5% in serum over 48 h. Cell binding was significant (>0.79). In vitro internalization reached up to %12-13 in 10 h. Significant tumor uptake was observed. Conclusions: In vitro and in vivo/SPECT imaging in SkBr3-bearing mice demonstrated that 111 In-DOTA-trastuzumab is a potential compound for molecular imaging of SPECT for diagnosis and follow-up of HER2 expression in oncology.

Abstract in Chinese

铟111标记的曲妥珠单抗临床试验的前期临床试验评估 背景:赫赛汀及其片段被同位素标记后用于人表皮生长因子受体2(HER2)/neu阳性肿瘤的成像,以及诊断配件的发展在放射性药物学中都有重要地位。 目的:本研究中,铟111-1,4,7,10-轮环藤宁 -1,4,7,10-四乙酸酸曲妥珠单抗依次准备和评估最终用于肿瘤学中HER2抗原成像。 方法设计:事先准备好结合配对,做好标签,离体评估(ELISA法)/(SPECT法)。 材料和方法:准备好铟111标记的曲妥珠单抗,测定放射化学纯度(RCP),蛋白完整性,放射性同位素标记抗体HER2/neu抗原的免疫反应性(SkBr3细胞株整合和RIA法),随后进行稳定性试验,内化研究和组织生物分布测定,对像包括野生大鼠和SPECT成像的SkBr3小鼠。 统计方法:所有值表示为平均值±标准差,用t-检验。显著性差异定义P<0.05。 结果:铟111标记的曲妥珠单抗(RCP >95 ± 0.5%, S.A. 5.3 μCi/μg),每抗体平均螯合剂6:1有明显的免疫反应性(ELISA法)。48小时离体稳定性:在磷酸盐缓冲盐水中>90%,血清中80% ± 0.5%。细胞整合明显:(>0.79)。10小时离体内化率12%~13%。可观察到明显的肿瘤摄取。 结论:在SkBr3小鼠离体和体内的/SPECT成像表明,铟111标记的曲妥珠单抗在肿瘤学HER2表达的诊断和随访、SPECT分子成像方面是一种有潜在功能的化合物。 关键词:生物学分布,铟111,生成,SkBr3细胞,单光子发射计算体层摄影,曲妥珠单抗



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