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The present article describes the preparation, characterization, and biological evaluation of Thulium-170 ((170)Tm) [T1/2 = 128.4 days; Eβmax = 968 keV; Eγ = 84 keV (3.26%)] labeled tin oxide microparticles for its possible use in radiation synovectomy (RSV) of medium-sized joints. (170)Tm was produced by irradiation of natural thulium oxide target. 170Tm-labeled microparticles were synthesized with high yield and radionuclidic purity (> 99%) along with excellent in vitro stability by following a simple process. Particle sizes and morphology of the radiolabeled particles were examined by light microscope, dynamic light scattering, and transmission electron microscope and found to be of stable spherical morphology within the range of 1.4-3.2 μm. The preparation was injected into the knee joints of healthy Beagle dogs intraarticularly for biological studies. Serial whole-body and regional images were taken by single-photon-emission computed tomography (SPECT) and SPECT-CT cameras up to 9 months postadministration, which showed very low leakage (< 8% of I.D.) of the instilled particles. The majority of leaked radiocolloid particles were found in inguinal lymph nodes during the 9 months of follow-up. All the animals tolerated the treatment well; the compound did not show any possible radiotoxicological effect. These preliminary studies showed that 170Tm-labeled microparticles could be a promising nontoxic and effective radiopharmaceutical for RSV applications or later local antitumor therapy.

Minigastrin (MG) analogues specifically target cholecystokinin-2 receptors (CCK2R) expressed in different tumours and enable targeted radiotherapy of advanced and disseminated disease when radiolabelled with a beta emitter such as 177Lu. Especially truncated MG analogues missing the penta-Glu sequence are associated with low kidney retention and seem therefore most promising for therapeutic use. Based on [D-GluM1,desGlu2-6]MG (MG11) we have designed the two cyclic MG analogues cyclo1,9[γ-D-GluM1,desGlu2-6,D-Lys9]MG (cyclo-MG1) and cyclo1,9[γ-D-Glu1,desGlu2-6,D-Lys9,Nle11]MG (cyclo-MG2). In the present work we have developed and preclinically evaluated a pharmaceutical kit formulation for the labelling with 177Lu of the two DOTA-conjugated cyclic MG analogues. The stability of the kits during storage as well as the stability of the radiolabelled peptides was investigated. A cell line stably transfected with human CCK2R and a control cell line without receptor expression were used for in vitro and in vivo studies with the radioligands prepared from kit formulations. In terms of stability 177Lu-DOTA-cyclo-MG2 showed advantages over 177Lu-DOTA-cyclo-MG1. Still, for both radioligands a high receptor-mediated cell uptake and favourable pharmacokinetic profile combining receptor-specific tumour uptake with low unspecific tissue uptake and low kidney retention were confirmed. Investigating the therapy efficacy and treatment toxicity in xenografted BALB/c nude mice a receptor-specific and comparable therapeutic effect could be demonstrated for both radioligands. A 1.7- to 2.6-fold increase in tumour volume doubling time was observed for receptor-positive tumours in treated versus untreated animals, which was 39-73% higher when compared to receptor-negative tumours. The treatment was connected with transient bone marrow toxicity and minor signs of kidney toxicity. All together the obtained results support further studies for the clinical translation of this new therapeutic approach.

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