A thermodynamic approach, using speciation studies, towards the evaluation and design of bone-seeking radiopharmaceuticals as illustrated for 117mSn(II)-PEI-MP

Blood plasma modeling has proved effective in the evaluation of clinical observations recorded for baboon and rat tests with ¹⁵³Sm- ethylenediaminetetraphosphonic acid (EDTMP) as well as for ¹⁶⁶Ho-EDTMP. In the search for a cure for metastatic bone cancer, ^117mSn with its conversion electrons of discrete energies shows low bone marrow toxicity, providing the opportunity to increase the administered dose. Selective accumulation in lesions would capitalize on this advantage. The 10-30 kDa fraction of the water-soluble polymer polyethyleneimine, functionalized with methylene phosphonate groups (PEI-MP) and labeled with ^99mTc, has shown selective uptake into bone tumours. This paper relates the speciation of Sn(II)-PEI-MP and other known ^117mSn(II) containing bone-seeking radiopharmaceuticals in blood plasma. Apparent formation constants for the complexation of Sn^II with PEI-MP, DTPA, HEDP and other important blood plasma ligands were measured potentiometrically or estimated by linear free energy relationships (LFER). These data were added to the ECCLES database in order to construct a blood plasma model for Sn^II. From this model it is predicted that Sn^II will remain bound to the polymer (PEI-MP) in blood plasma and therefore, have only slight reticuloendothelial uptake. Preliminary primate studies indeed proved that the complex between Sn^II and PEI-MP remains intact in blood plasma, which is consistent with the observation for PEI-MP labeled with ^99mTc. From these data, it was also possible to explain in retrospect the lower bone uptake, the slow blood clearance and the liver uptake of the agents ^117mSn(II) DTPA and ^117mSn(II) HEDP agents as reported in the literature.