An In Vitro Instead of In Vivo Approach to Develop 117MSN Based Bone-Seeking Radiopharmaceuticals as Studied for SN(II) and SN(IV) Complexes of the Polymer Polyethyleneiminomethyl Phosphonic Acid (PEI-MP)

It has become standard practice in the development of radiopharmaceuticals to evaluate/assess the efficacy of prospective therapeutic or diagnostic agents by animal models, which generally calls for subjecting a substantial number of animals to intensive test and retest measurements for obtaining representative and conclusive results. This work communicates the advantage of combining various analytical modalities with mathematical and computational modelling as a multifaceted tool, for pre-vivo screening of prospective radiopharmaceuticals intended for the treatment of metastases in bone. In an attempt to improve the tumour selectivity and uptake of phosphonates, the novel water soluble phosphonate polymer PEI-MP (N,N',N'-trimethylenephosphonate-polyethyleneimine) was studied, exploiting a phenomenon known as the Enhanced Permeation and Retention effect (EPR), whereby macromolecules, e.g. polymers, selectively accumulate within tumours due to irregularities in the vasculature and poor lymphatic clearance. 117mSn (t1/2=13.6d) could prove to be a promising therapeutic radionuclide in that it emits mono-energetic Auger and conversion electrons with a discrete range (0.2-0.3mm) in bone tissue, allowing for larger bone radiation doses with limited radiotoxicity to bone marrow. It also emits a gamma (159keV, 86.4%) which could allow for visualisation of treatment localisation. The aspects covered in the pre-vivo assessment were; 1) The oxidation state of the metal ion as the fate of the drug-complex may depend on the valence stability of the metal-ion in vivo. It was proven that Sn2+ and Sn4+ do not interchange in conditions simulating blood plasma 2) Using glass electrode potentiometry, the complexes with the most prominent physiological metal ions, namely Ca2+, Mg2+, Zn2+ with PEI-MP were studied and after compilation of a Sn2+ and Sn4+ blood plasma model, PEI-MP complexed with Sn2+ proved to be the superior combination. 3) Concurrently the same combinations were tested for their adsorption characteristics with hydroxyapatite, which served as an in vitro model for bone mineral. The ideal combination for optimum complex adsorption was determined, taking into account the polymer, with size fractions of 10-30kDa or 30-50kDa, and the particular valence form of tin. The Sn2+-PEI-MP complex, with a polymer size of 10-30kDa, was best. (author)