Preclinical comparison of (radio)lanthanides using mass spectrometry and nuclear imaging techniques: biodistribution of lanthanide-based tumor-targeting agents and lanthanides in ionic form

Abstract

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.