ИСТИНА

Radionuclide therapy, based on the use of α- and β-emitting radionuclides for labeling compounds with the ability of targeted delivery to a cancer cell, is currently one of the most promising methods for the treatment of oncological diseases. 212Pb is of particular concern, since it is a β-emitter, but its daughter radionuclides 212Bi and 212Po undergo α-decay, whereby 212Pb is to be considered as an in vivo α-particle generator. In this regard, a method for the synthesis of a labeled complex based on a synthetic peptide octreotate conjugated with a bifunctional chelating agent DOTA was developed. The octreotate-DOTA (DOTATATE) complex was labeled with 210Pb and 212Pb radionuclides. A search for the most suitable conditions of thin-layer chromatography application for determination of the radiochemical yield of labeling reactions was carried out with more long-lived isotope 210Pb which was extracted with the use of extraction chromatography on Sr-resin (Triskem Inc.) according to the technique described in numerous papers. The radionuclide 212Pb was produced using the developed 228Th / 212Pb generator. Its principle is based on the removal from the volume of 228Th-containing ion exchange DOWEX resin gaseous 220Rn into a separate collector vessel with air flow. After its decay, formed 212Pb is washed out from the collector with a solution of 0.1 M HCl. Due to this phase separation, a high radionuclide purity of the preparation is provided, which plays an important role in nuclear medicine applications. After each production cycle of 72 hours, the activity of the produced isotope is approximately 1 MBq. Herein the labeling conditions such as peptide amount and synthesis time were varied to study the dependence of the DOTATATE labeling yield on this conditions. It was found that the 212Pb-DOTATATE complex is formed with high efficiency at a temperature of 90°C, an incubation time of 15 minutes and pH values of 5.0-6.5. The specific activity was 0.05 MBq / nmol of peptide. Investigations have also been carried out to show the dissociative stability of the synthesized complex in isotonic solution. It was shown that the stability of the complex reamains at> 95% throughout the half-life of 212Pb (10.64 h). The labeling yield, as well as the stability of the complex in isotonic solution, was determined by thin layer chromatography. Investigations also were carried out to determine the stability of the complex in human serum. Serum was obtained from the blood of healthy donor. Following dilution the complex in serum, aliquots were taken from mixture after definite time intervals (1, 3, 6, 10 h), then serum proteins were denatured by adding 96% ethanol, followed by precipitation of proteins by centrifugation for 5 minutes (5000g). The value of stability was determined by the ratio of activity in the supernatant (unrelated to protein activity) to the initial activity in the aliquot. Experiments have shown that the stability amounts from 80% to 90% up to 10 hours. Thus, a large proportion of the complex retains its therapeutic potential in the blood serum substance. The results obtained allow regarding the 212Pb-DOTATATE complex as a promising radiopharmaceutical which opens the pathway to possible studies of the specificity of bounding with SSTR2-containing cells, cytotoxicity, and preparation biodistribution. Further, the complex can be considered as one of the tools for the treatment of neuroendocrine tumors, as well as other oncological diseases.