Design and synthesis of [In-111]DTPA-folate for use as a tumor-targeted radiopharmaceutical
Design and synthesis of [In-111]DTPA-folate for use as a tumor-targeted radiopharmaceutical
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DOI：
10.1021/bc9701297
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发表时间：
1997-09-01
影响因子：
4.7
通讯作者：
Low, PS
中科院分区：
文献类型：
--
作者：
Wang, S;Luo, J;Low, PS
叶酸结合的金属螯合物已被提议作为过度表达叶酸受体的癌症的潜在成像剂。在之前的一项研究中，叶酸通过其 γ-羧基与去铁胺 (DF) 连接，并在植入人肿瘤细胞的无胸腺小鼠中检查了 Ga-67 标记复合物（[Ga-67]DF-叶酸）的体内肿瘤靶向效率。尽管获得了极好的肿瘤与背景对比度，但肝胆清除缓慢会影响卵巢癌等腹部肿瘤的成像。在本研究中，叶酸通过乙二胺间隔基与替代螯合剂二亚乙基三胺五乙酸（DTPA）缀合。所需的 DTPA-叶酸（γ）区域异构体通过两种不同的方法合成，通过反相柱色谱纯化，并主要通过分析型 HPLC、质谱和 NMR 进行表征。在培养的肿瘤细胞中，[In-111]DTPA-叶酸（γ）的摄取被发现对叶酸受体携带细胞具有特异性，并且摄取动力学与游离叶酸和其他叶酸结合分子的摄取动力学相似。在正常大鼠中，静脉注射[In-111]DTPA-叶酸(γ)被发现迅速排泄到尿液中，4小时时肠道内放射性示踪剂水平比[Ga-67]DF-叶酸(γ)观察到的水平低10倍。在一项初步的小鼠成像研究中，静脉注射[In-111]DTPA-叶酸(gamma)后1小时，叶酸受体阳性的KB细胞肿瘤很容易通过伽马闪烁扫描术观察到。
Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the Ga-67-labeled complex ([Ga-67]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate(gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [In-111]DTPA-folate(gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [In-111]DTPA-folate(gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [Ga-67]DF-folate(gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy I h following intravenous administration of [In-111]DTPA-folate(gamma).