Purpose

With the growing interest in exploring radiolanthanides for nuclear medicine applications, the question arises as to whether they are generally interchangeable without affecting a biomolecule’s pharmacokinetic properties. The goal of this study was to investigate similarities and differences of four (radio)lanthanides simultaneously applied as complexes of biomolecules or in ionic form.

Methods

Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the simultaneous detection of four lanthanides (Ln = lutetium, terbium, gadolinium and europium) in biological samples. In vitro tumor cell uptake and in vivo biodistribution studies were performed with Ln-DOTATATE, Ln-DOTA-LM3, Ln-PSMA-617 and Ln-OxFol-1. AR42J cells, PC-3 PIP cells and KB cells expressing the somatostatin receptor, the prostate-specific membrane antigen and the folate receptor, respectively, were used in vitro as well as to obtain the respective tumor mouse models for in vivo studies. The distribution of lanthanides in ionic form was investigated in immunocompetent mice. Dual-isotope SPECT/CT imaging studies were performed with mice administered with the radiolabeled biomolecules or chloride salts of lutetium-177 and terbium-161.

Results

Similar in vitro cell uptake was observed for all four lanthanide complexes of each biomolecule into the respective tumor cell lines. AR42J tumor uptake of Ln-DOTATATE and Ln-DOTA-LM3 in mice showed similar values for all lanthanide complexes (3.8‒5.1% ID/g and 4.5‒5.0% ID/g; 1 h p.i., respectively). Accumulation of Ln-PSMA-617 in PC-3 PIP tumors (24–25% ID/g; 1 h p.i.) and of Ln-OxFol-1 in KB tumors (28–31% ID/g; 24 h p.i.) were also equal for the four lanthanide complexes of each biomolecule. After injection of lanthanide chloride salts (LnCl₃; Ln = ^natLu, ^natTb, ^natGd, ^natEu), the liver uptake was different for each metal (~ 12% ID/g, ~ 22% ID/g, ~ 31% ID/g and ~ 37% ID/g; 24 h p.i., respectively) which could be ascribed to the radii of the respective lanthanide ions. In the bones, accumulation was considerably higher for lutetium than for other lanthanides (25 ± 5% ID/g vs. 14‒15% ID/g; 24 h p.i.). These data were confirmed visually by ¹⁷⁷Lu/¹⁶¹Tb-based dual-isotope SPECT/CT images.

Conclusions

The presented study confirmed similar properties of Ln-complexes, suggesting that lutetium-177 can be replaced by other radiolanthanides, most probably without affecting the tissue distribution profile of the resultant radiopharmaceuticals. On the other hand, the different radii of the lanthanide ions affected their uptake and resorption mechanisms in liver and bones when injected in uncomplexed form.

中文翻译：

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使用质谱和核成像技术对（放射性）镧系元素进行临床前比较：基于镧系元素的肿瘤靶向剂和离子形式的镧系元素的生物分布

 目的

随着人们对探索放射性镧系元素用于核医学应用的兴趣日益浓厚，出现了一个问题，即它们是否通常可以互换而不影响生物分子的药代动力学特性。本研究的目的是研究四种（放射性）镧系元素同时作为生物分子复合物或以离子形式应用的异同。

 方法

采用电感耦合等离子体质谱法 （ICP-MS） 同时检测生物样品中的四种镧系元素 （Ln = 镥、铽、钆和铕）。用 Ln-DOTATATE 、 Ln-DOTA-LM3 、 Ln-PSMA-617 和 Ln-OxFol-1 进行体外肿瘤细胞摄取和体内生物分布研究。分别表达生长抑素受体、前列腺特异性膜抗原和叶酸受体的 AR42J 细胞、PC-3 PIP 细胞和 KB 细胞在体外使用，以及获得用于体内研究的相应肿瘤小鼠模型。研究了离子形式的镧系元素在免疫功能正常的小鼠中的分布。对小鼠进行双同位素 SPECT/CT 成像研究，给予放射性标记的生物分子或镥 177 和铽 161 的氯化物盐。

 结果

观察到每个生物分子的所有四种镧系元素复合物在体外细胞摄取到相应的肿瘤细胞系中。小鼠中 AR42J 肿瘤对 Ln-DOTATATE 和 Ln-DOTA-LM3 的摄取对所有镧系元素复合物均显示出相似的值（分别为 3.8-5.1% ID/g 和 4.5-5.0% ID/g;1 h p.i.）。Ln-PSMA-617 在 PC-3 PIP 肿瘤中的积累（24-25% ID/g;1 小时 p.i.）和 Ln-OxFol-1 在 KB 肿瘤中的积累（28-31% ID/g;24 h p.i.）对于每个生物分子的四种镧系元素复合物也相等。注射镧系氯化物盐 （LnCl₃;Ln = ^natLu、^natTb、^natGd、^natEu），每种金属的肝脏摄取不同（分别为 ~ 12% ID/g、~ 22% ID/g、~ 31% ID/g 和 ~ 37% ID/g;24 h p.i.），这可能归因于各自镧系元素离子的半径。在骨骼中，镥的积累量远高于其他镧系元素（25 ± 5% ID/g vs. 14-15% ID/g;24 小时 p.i.）。这些数据通过基于 ¹⁷⁷Lu/¹⁶¹Tb 的双同位素 SPECT/CT 图像目测证实。

 结论

本研究证实了 Ln 配合物的相似特性，表明镥 177 可以被其他放射性镧系元素取代，很可能不会影响所得放射性药物的组织分布概况。另一方面，当以未络合形式注射时，镧系元素离子的不同半径会影响它们在肝脏和骨骼中的摄取和吸收机制。