Promises of Cyclotron-Produced 44Sc as a Diagnostic Match for Trivalent β--Emitters: In Vitro and In Vivo Study of a 44Sc-DOTA-Folate Conjugate
Promises of Cyclotron-Produced 44Sc as a Diagnostic Match for Trivalent β--Emitters: In Vitro and In Vivo Study of a 44Sc-DOTA-Folate Conjugate
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DOI：
10.2967/jnumed.113.123810
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发表时间：
2013-12-01
影响因子：
9.3
通讯作者：
Schibli, Roger
中科院分区：
文献类型：
--
作者：
Mueller, Cristina;Bunka, Maruta;Schibli, Roger
近年来，Ga-68-放射性金属化肽用于癌症PET成像引起了临床医生的关注。在此，我们建议使用 Sc-44（半衰期 = 3.97 h，平均 beta(+) 能量 [E beta(+)(av)] = 632 keV）作为 Ga-68（半衰期 = 68 分钟，E beta(+)(av) = 830 key）的有价值的替代品，用于在基于 Lu-177 的放射性核素治疗之前进行成像和剂量测定。该研究的目的是对回旋加速器产生的 Sc-44 标记的叶酸缀合物进行临床前评估，并与 Lu-177 标记的悬垂物进行体外和体内比较。方法：使用富集的 Ca-44 靶标（10 mg (CaCO3)-Ca-44，97.00%），通过回旋加速器（17.6 +/- 1.8 MeV，50 mu A，30 分钟）的 Ca-44(p,n)Sc-44 核反应产生 Sc-44。使用萃取色谱法和阳离子交换色谱法通过半自动过程进行与目标材料的分离。 DOTA-叶酸缀合物 (cm09) 的放射性标记在 95°C 下 10 分钟内进行。 Sc-44-cm09 的稳定性在人血浆中进行了测试。使用叶酸受体阳性 KB 肿瘤细胞对 Sc-44-cm09 进行体外研究，并通过荷瘤小鼠的 PET/CT 成像进行体内研究结果：在给定的照射条件下，以高放射性核素纯度 (>99%) 获得 Sc-44 的最大产量为 350 MBq。从 Ca-44 靶标中半自动分离 Sc-44 可以在 10 分钟内在 200-400 μL 醋酸铵/HCl 溶液（1 M，pH 3.5-4.0）体积中配制高达 300 MBq 的 Sc-44。 cm09 的放射性标记实现了放射化学产率大于 96%，比活度为 5.2 MBq/nmol。在体外，Sc-44-cm09 在整个研究期间在人血浆中保持稳定，并显示出叶酸受体与 KB 肿瘤细胞的特异性结合。注射 Sc-44-cm09 的小鼠的 PET/CT 图像可以实现肿瘤异种移植物的良好可视化。用 Sc-44 和 Lu-177 标记的 cm09 的比较揭示了几乎相同的药代动力学。结论：本研究提出了一种高产率生产和高效分离 Sc-44 的方法，其质量适合 DOTA 功能化生物分子的放射性标记。使用 DOTA-叶酸缀合物进行的体内概念验证研究证明了 Sc-44 在 PET 成像方面的优异特性。因此，Sc-44 是 Ga-68 的有效替代品，用于 Lu-177-放射性核素肿瘤治疗之前的成像和剂量测定。
In recent years, implementation of Ga-68-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of Sc-44 (half-life = 3.97 h, average beta(+) energy [E beta(+)(av)] = 632 keV) as a valuable alternative to Ga-68 (half-life = 68 min, E beta(+)(av) = 830 key) for imaging and dosimetry before Lu-177-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced Sc-44 and its in vitro and in vivo comparison with the Lu-177-labeled pendant. Methods: Sc-44 was produced via the Ca-44(p,n)Sc-44 nuclear reaction at a cyclotron (17.6 +/- 1.8 MeV, 50 mu A, 30 min) using an enriched Ca-44 target (10 mg (CaCO3)-Ca-44, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95 degrees C within 10 min. The stability of Sc-44-cm09 was tested in human plasma. Sc-44-cm09 was investigated in vitro using folate receptor-positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice Results: Under the given irradiation conditions, Sc-44 was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of Sc-44 from Ca-44 targets allowed formulation of up to 300 MBq of Sc-44 in a volume of 200-400 mu L of ammonium acetate/HCl solution (1 M, pH 3.5-4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, Sc-44-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor-specific binding to KB tumor cells. PET/CT images of mice injected with Sc-44-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with Sc-44 and Lu-177 revealed almost identical pharmacokinetics. Conclusion: This study presents a high-yield production and efficient separation method of Sc-44 at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of Sc-44 for PET imaging. Thus, Sc-44 is a valid alternative to Ga-68 for imaging and dosimetry before Lu-177-radionuclide tumor therapy.