Biodistribution and biospeciation of samarium-153 chelates

Tumour localisation and biodistribution of several samarium-153 complexes have been investigated by evaluation of the speciation of these complexes in blood plasma using potentiometric titration data and computer modelling. Furthermore, the results of the simulations have been used to propose explanations of the observed biodistributions. Tissue distribution studies were used to evaluate the localisation of the samarium-153 complexes of the ligands DTPA, HEDTA, HIDA, BZ, PBH, PIH, NTA, citrate and chloride in C57/6J black mice bearing either melanotic or amelanotic B16 melanomas. The mice were sacrificed at 1, 6, 24 or 48 hours after injection and the tumours and other organs of interest removed and measured for radioactivity against a known standard. Tumour imaging studies were also performed. Appreciable tumour uptake was achieved with all of the complexes, with the exception of Sm-DTPA although the degree of uptake was less than that of gallium-67 citrate. Visualisation of the tumours after administration of many of the samarium-153 complexes was precluded by a high degree of hepatic localisation. The most favourable images were obtained after administration of 153Sm-HEDTA, with the implanted tumour being visible at all times in images performed from 1 to 48 hours. In order to further understand the bioinorganic chemistry of samarium in the presence of such chelating agents, the protonation constants of citric acid, HEDTA, EDTMP and salicylic acid, as well as the formation constants of their complexes with samarium(III) and yttrium(III), were measured by potentiometric titration and the data analysed using the ESTA suite of programs. The distribution of these complexes as a function of pH was also calculated. The results obtained from the potentiometric studies were incorporated in blood plasma modelling using the computer program ECCLES to determine both the relative strengths of the complexes in aqueous solution and their speciation in blood plasma. Simulation results indicate that, in aqueous solution, HEDTA is the strongest of the complexing agents for both samarium(III) and yttrium(III) while citrate is the weakest. The complexes of yttrium(III) appear to be generally weaker than those of samarium(III). The ligand HEDTA is also the most effective complexing agent in vivo. Computer simulations also indicate that samarium is predominantly complexed as the [SmCit]0 and [SmHEDTA]0 species when administered with citrate and HEDTA, respectively. The formation of these neutral species accounts for the high degree of hepatic localisation observed in the biodistribution studies. In contrast, the major samarium species formed with EDTMP appear to be [SmEDTMP]5- [Sm(EDTMP)H-1]6-. The formation of these charged species would explain why the and complex is excreted almost exclusively via the kidneys. The major competitive interactions for the complexes of Sm-HEDTA in vivo appear to be those of endogenous ligands for the metal ion. In the case of Sm-EDTMP, however, competition for the ligand by endogenous calcium ions takes precedence. This suggests a possible mechanism for the observed localisation of 153Sm-EDTMP in bone metastases