Biodistribution and kinetics were studied of potentially target biospecific radiopharmaceutical medication for the treatment of malignant tumors of various histologic type and location with expression of cytotoxic T-lymphocyte membrane associated glycoprotein 4 and glucocorticoid Induced Tumor Necrosis Factor Receptor) 177Lu-DOTA-anti-CTLA4-GITR. Colorectal cancer experimental model has been successfully reproduced by means of murine large intestine experimental adenocarcinoma cells (AKATOL) СТ26 EGFR) direct transplantation. The model was characteristic of moderate growth rate and practically complete absence of metastatic spread. Immunohistochemical assay of tumor tissue has revealed satisfactory expression level of target antigens for the medication under study, i.e. cytotoxic T-lymphocyte associated protein 4 (CTLA4) as well as membrane receptor of tumor necrosis factor group (GITR). This medication 177Lu-DOTA-anti-CTLA4-GITR has been shown to store in the tumor tissue. Its major pathways out of the organism were through urinary system. On the other hand, the medication has also been demonstrated to store in non-target tissues, namely: kidneys, liver, large intestine. The results of this study may be used in preclinical studies of medications and serve as a basis for broader studies of 177Lu-DOTA-anti-CTLA4-GITR and its safety.

The aim of the study is assessment of combined effect of homotransplanted rat lymphoma (Pliss Lymphosrcoma) growth and antitumor therapy (cysplatin) upon the functioning of the nervous system was accomplished in 160 male Wistar rats, divided into four groups: intact animals, rats treated with cysplatin, rats with transplanted lymphoma, and rats with transplanted lymphoma that received cysplatin treatment. The neurologic deficiency degree as well as basic myelin protein peripheral blood level (nervous system impairment hematological marker) were comparatively assessed. Tumor development was accompanied with emergence and subsequent growth of neurologic deficit in locomotory, sensory and coordinative spheres as well as pronounced growth of basic myeline protein plasma level thus making this model a valid test-system for studying paraneoplastic neurologic syndrome. Cysplatin has produced a non-selective toxic effect upon the nervous system of the experimental animals within its therapeutic window range documented by neurotoxic syndrome. Subsequently along with elimination of cysplatin and its derivates from the organism, systemic neurotoxic effect intensity decreased and the nervous system functional state parameters returned to control values. Using cysplatin for the treatment of homotransplanted experimental rat lymphoma results in synergic neurotoxic and paraneoplastic neurological syndrome through combined injury of the nervous system.

Radiopharmaceutical targeted medication based on biospecific antibodies to tumor-associated stroma elements and 177lutecium (177Lu-DOTA-anti-CTLA4-GITR) potential anti-tumor activity was studied in two courses: one-time administration and two injections with a considerable lag. Subcutaneously transplanted experimental colonic carcinoma (AKATOL; cell line CT26 EGFP) with high expression of green fluorescent protein (eGFP) and additional expression of target tumor-associated stroma molecules CTLA4 and GITR was used as a model in BALB/c male mice. The experimental radiopharmaceutical targeted medication proved to possess high pharmacologic activity against the tumor under study. It was apparent in valid increase of experimental animals mean lifespan, tumor debut latent period inhibition and clinically valid tumor growth rate slowdown. Double administration of 177Lu-DOTA-anti-CTLA4-GITR proved to be more effective than one-time one, however neither of them managed to yield statistically valid difference in safety levels.