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[99mTc]Tc-DTPA-Bis(cholineethylamine) as an Oncologic Tracer for the Detection of Choline Transporter (ChT) and Choline Kinase (ChK) Expression in Cancer
ACS Omega ( IF 3.7 ) Pub Date : 2022-04-08 , DOI: 10.1021/acsomega.1c04256 Ambika Parmar Jaswal 1 , Puja Panwar Hazari 1 , Surbhi Prakash 1 , Pallavi Sethi 1 , Aruna Kaushik 2 , Bal G Roy 3 , Swati Kathait 1 , Baljinder Singh 4 , Anil Kumar Mishra 1
ACS Omega ( IF 3.7 ) Pub Date : 2022-04-08 , DOI: 10.1021/acsomega.1c04256 Ambika Parmar Jaswal 1 , Puja Panwar Hazari 1 , Surbhi Prakash 1 , Pallavi Sethi 1 , Aruna Kaushik 2 , Bal G Roy 3 , Swati Kathait 1 , Baljinder Singh 4 , Anil Kumar Mishra 1
Affiliation
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Objective: The elevated choline transporters (ChT), choline kinase (ChK), choline uptake, and phosphorylation in certain tumor cells have influenced the development of radiolabeled choline derivatives as diagnostic probes for imaging cell membrane proliferation. We, therefore, aimed to develop a choline-based moiety for imaging choline kinase-overexpressed tumors by single-photon emission tomography (SPECT). A novel choline-based diagnostic probe was synthesized and evaluated preclinically in various ChT- and ChK-overexpressed tumor models for SPECT imaging applications. Methods: The synthesis of diethylenetriaminepentaacetic acid-bis-choline ethylamine [DTPA-bis(ChoEA)] featured the conjugation of dimethylaminoethanol to a bifunctional chelator DTPA anhydride. [99mTc]Tc-DTPA-bis(ChoEA) was prepared, and its in vivo characteristics were evaluated in BALB/c mice and tumor-xenografted PC3, A549, and HCT116 athymic mouse models. The in vitro parameters, including cell binding and cytotoxicity, were assessed in PC3, A549, and HCT116 cell lines. To evaluate the specificity of the radioprobe, competitive binding studies were performed. Small-animal SPECT/CT diagnostic imaging was performed for in vivo evaluation. The mouse biodistribution data was further investigated to estimate the radiation dose in humans. Results: In silico studies suggested high binding with enhanced specificity. A standard radiolabeling procedure using stannous chloride as a reducing agent showed a labeling yield of 99.5 ± 0.5%. The in silico studies suggested high binding with enhanced specificity. [99mTc]Tc-DTPA-bis(ChoEA) showed high in vitro stability and specificity. The pharmacokinetic studies of [99mTc]Tc-DTPA-bis(ChoEA) in mice showed an increased tumor-to-background ratio after few minutes of intravenous administration. The first-in-human trial was also conducted. The effective dose was estimated to be 0.00467 mSv/MBq (4.67 mSv/GBq), resulting in a radiation dose of up to 1.73 mSv for the 370 MBq injection of [99mTc]Tc-DTPA-bis(ChoEA). Conclusions: The synthesized radioprobe [99mTc]Tc-DTPA-bis(ChoEA) accumulates specifically in choline kinase-overexpressed tumors with a high signal-to-noise ratio. The preclinical and first-in-man data suggested that [99mTc]Tc-DTPA-bis(ChoEA) could potentially be used as a diagnostic SPECT tracer in the monitoring and staging of cancer.
中文翻译：
[99mTc]Tc-DTPA-Bis(cholineethylamine) 作为肿瘤示踪剂用于检测癌症中胆碱转运蛋白 (ChT) 和胆碱激酶 (ChK) 的表达
目的：某些肿瘤细胞中升高的胆碱转运蛋白 (ChT)、胆碱激酶 (ChK)、胆碱摄取和磷酸化影响了放射性标记胆碱衍生物作为细胞膜增殖成像诊断探针的发展。因此，我们旨在开发一种基于胆碱的部分，用于通过单光子发射断层扫描 (SPECT) 对胆碱激酶过度表达的肿瘤进行成像。在各种 ChT 和 ChK 过表达的肿瘤模型中合成和评估了一种新型的基于胆碱的诊断探针，用于 SPECT 成像应用。方法：二亚乙基三胺五乙酸-双胆碱乙胺 [DTPA-bis(ChoEA)] 的合成以二甲氨基乙醇与双功能螯合剂 DTPA 酸酐的共轭为特征。[ 99m制备 Tc]Tc-DTPA-bis(ChoEA)，并在 BALB/c 小鼠和肿瘤异种移植的 PC3、A549 和 HCT116 无胸腺小鼠模型中评估其体内特性。在 PC3、A549 和 HCT116 细胞系中评估了体外参数，包括细胞结合和细胞毒性。为了评估放射性探针的特异性，进行了竞争性结合研究。进行了小动物 SPECT/CT 诊断成像以进行体内评估。进一步研究了小鼠的生物分布数据，以估计人类的辐射剂量。结果：计算机研究表明高结合性和增强的特异性。使用氯化亚锡作为还原剂的标准放射性标记程序显示标记率为 99.5 ± 0.5%。计算机研究表明具有增强的特异性的高结合。[ 99mTc]Tc-DTPA-bis(ChoEA) 表现出较高的体外稳定性和特异性。[ 99m Tc]Tc-DTPA-bis(ChoEA) 在小鼠体内的药代动力学研究表明，静脉给药几分钟后肿瘤与背景的比率增加。还进行了首次人体试验。有效剂量估计为 0.00467 mSv/MBq (4.67 mSv/GBq)，导致 370 MBq 注射 [ 99m Tc]Tc-DTPA-bis(ChoEA)的辐射剂量高达 1.73 mSv 。结论：合成的放射性探针 [ 99m Tc]Tc-DTPA-bis(ChoEA) 在胆碱激酶过度表达的肿瘤中特异性积累，具有高信噪比。临床前和首次人体试验数据表明 [ 99mTc]Tc-DTPA-bis(ChoEA) 可能用作癌症监测和分期的诊断 SPECT 示踪剂。
更新日期：2022-04-08
中文翻译：
[99mTc]Tc-DTPA-Bis(cholineethylamine) 作为肿瘤示踪剂用于检测癌症中胆碱转运蛋白 (ChT) 和胆碱激酶 (ChK) 的表达
目的：某些肿瘤细胞中升高的胆碱转运蛋白 (ChT)、胆碱激酶 (ChK)、胆碱摄取和磷酸化影响了放射性标记胆碱衍生物作为细胞膜增殖成像诊断探针的发展。因此，我们旨在开发一种基于胆碱的部分，用于通过单光子发射断层扫描 (SPECT) 对胆碱激酶过度表达的肿瘤进行成像。在各种 ChT 和 ChK 过表达的肿瘤模型中合成和评估了一种新型的基于胆碱的诊断探针，用于 SPECT 成像应用。方法：二亚乙基三胺五乙酸-双胆碱乙胺 [DTPA-bis(ChoEA)] 的合成以二甲氨基乙醇与双功能螯合剂 DTPA 酸酐的共轭为特征。[ 99m制备 Tc]Tc-DTPA-bis(ChoEA)，并在 BALB/c 小鼠和肿瘤异种移植的 PC3、A549 和 HCT116 无胸腺小鼠模型中评估其体内特性。在 PC3、A549 和 HCT116 细胞系中评估了体外参数，包括细胞结合和细胞毒性。为了评估放射性探针的特异性，进行了竞争性结合研究。进行了小动物 SPECT/CT 诊断成像以进行体内评估。进一步研究了小鼠的生物分布数据，以估计人类的辐射剂量。结果：计算机研究表明高结合性和增强的特异性。使用氯化亚锡作为还原剂的标准放射性标记程序显示标记率为 99.5 ± 0.5%。计算机研究表明具有增强的特异性的高结合。[ 99mTc]Tc-DTPA-bis(ChoEA) 表现出较高的体外稳定性和特异性。[ 99m Tc]Tc-DTPA-bis(ChoEA) 在小鼠体内的药代动力学研究表明，静脉给药几分钟后肿瘤与背景的比率增加。还进行了首次人体试验。有效剂量估计为 0.00467 mSv/MBq (4.67 mSv/GBq)，导致 370 MBq 注射 [ 99m Tc]Tc-DTPA-bis(ChoEA)的辐射剂量高达 1.73 mSv 。结论：合成的放射性探针 [ 99m Tc]Tc-DTPA-bis(ChoEA) 在胆碱激酶过度表达的肿瘤中特异性积累，具有高信噪比。临床前和首次人体试验数据表明 [ 99mTc]Tc-DTPA-bis(ChoEA) 可能用作癌症监测和分期的诊断 SPECT 示踪剂。
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