Background. The solubility of active pharmaceutical ingredients (API) in water is one of the main factors affecting their bioavailability. Various methods are used to improve solubilation, including micronization and the creation of solid dispersions. The use of the method of rapid expansion of supercritical fluids makes it possible to combine the positive properties of micronization and the creation of solid dispersions, however, most APIs are insoluble in the main compound used to create the fluid – carbon dioxide. For this reason, the method of crystallization under supercritical antisolvent (SAS) conditions has been developed, which makes it possible to micronization and create solid dispersions of compounds insoluble in carbon dioxide.

Aim. The analysis of modern achievements in the field of creating solid dispersions (SD) using an analogue of the method of rapid expansion of supercritical liquids – the SAS method, where the liquid is used as an anti-solvent, which significantly expands the possibilities of using this approach.

Results. The use of SAS technology to create SD makes it possible to improve the solubility of API by amorphizing it and ensuring solubility at a level above the equilibrium value. As a polymeric carrier in SD, polyvinylpyrrolidone and hydroxypropylmethylcellulose are mainly used, while as a surfactant, Pluronic® F-127 is employed, which represents a copolymer consisting of ethylene oxide and polypropylene units. Ethanol or methanol is often used as a solvent, including in a mixture with dichloroethane or methylene chloride.

Conclusion. Improving the solubility of API by creating a SD using the SAS method can significantly increase the kinetics of dissolution. Despite its relevance, the process of creating a TD using the SAS method is quite complex, depending both on the API, the polymers and surfactants used, as well as on the process parameters and characteristics, ranging from process temperature and pressure to the mass transfer rate and the shape of the reactor and nozzle.

Background. Cytological examination of cerebrospinal fluid (CSF) and the dynamics of neurological symptoms are key in the diagnosis and evaluation of treatment effectiveness for leptomeningeal metastases. Quantitative assessment of circulating tumor cells in CSF is not routinely used. This study examined the correlation between the dynamics of tumor cell counts in CSF and the dynamics of neurological symptoms in patients with leptomeningeal metastases from breast cancer during intrathecal methotrexate therapy.

Aim. To identify clinical and cytological features in patients with leptomeningeal metastases from breast cancer during intrathecal methotrexate therapy.

Materials and methods. A retrospective analysis of 30 patients with leptomeningeal metastases from breast cancer who received intrathecal methotrexate in the Department of Neurooncology of the N. N. Blokhin National Medical Research Center of Oncology from 2018 to 2024.

Results. All 30 cases involved women with ductal or lobular breast cancer. The highest proportion of patients with leptomeningeal metastases were found in stage III–C breast cancer (33.3 %). Cytological analysis of cerebrospinal fluid and neurological status assessment were performed before each methotrexate administration. The correlation was monitored throughout the treatment period. A direct statistically significant relationship has been found between the number of tumor cells in cerebrospinal fluid and the severity of neurological disorders: at one month after treatment start r = 0.702; p = 0.000 and at two months r = 0.819; p = 0.000. However, prior to therapy initiation there was no correlation between these parameters (r = 0.056; p = 0.770). Thus, with a low level of tumor cytosis pronounced neurological symptoms could be present (75 cells, symptom score – 6 points), while conversely, with an elevated cytosis level mild neurological manifestations might occur (400 cells, symptom score – 3 points). It was found that only with a decrease in the number of tumor cells in the cerebrospinal fluid by 2 or more times (or by 50 %) does the severity of neurological disorders change. And an increase in the severity of neurological disorders occurs in the case of an increase in the number of cells in the cerebrospinal fluid by 1.2 times (or by 20 %). Moreover, this correlation was maintained throughout the treatment.

Conclusion. Evaluation of the dynamics of tumor cytosis in the cerebrospinal fluid, along with clinical characteristics, can be recommended for use in predicting the response to treatment in patients with leptomeningeal metastases of breast cancer.

Background. Antigen load, expression of programmed cell death ligand 1 and T-cell receptors play a key role in the formation of specific antitumor immunity. The marker of the diversity of the repertoire of receptors of immunocompetent cells to various antigens are T-cell receptor excision circles (TREC) and the κ-deletion B-cell receptor excision circles (KREC), which are extrachromosomal DNA structures.

Aim. To evaluate the effect of the diversity of TREC and KREC on the effectiveness of olaparib therapy for generalized ovarian cancer.

Materials and methods. The study included 40 patients undergoing treatment at the Republican Clinical Oncological Dispensary (RCOD) of the Ministry of Health of the Republic of Bashkortostan for ovarian cancer. The local ethics committee of RCOD approved on July 21, 2022 the protocol “IO-001” of a single-center nonrandomized open clinical trial entitled “Determination of TREC and KREC in patients with malignant neoplasms of various localizations”. All patients were prescribed olaparib therapy (international non-proprietary name). To identify mutations in genes associated with HRD (homologous recombination deficiency), next-generation sequencing by allele-specific polymerase chain reaction was used. Before the start of therapy, the level of TREC and KREC was assessed.

Results. Before the start of therapy in the general population, the median TREC was 9.6 copies / 105 cells, the median KREC was 183.8 copies / 105 cells. The minimum and maximum TREC levels were 0.07 copies / 105 cells and 215 copies / 105 cells, respectively. The minimum and maximum KREC levels were 2.8 copies / 105 cells and 1559.42 copies / 105 cells, respectively. In the group of patients with disease progression, the level of TREC was low. According to the results of the study, disease progression was predicted at a TREC value <13.23 copies / 105 cells. The obtained results indicate a significantly low level of KREC before the start of therapy in patients who progressed during therapy.

Conclusion. The prognostic role of TREC and KREC has been determined. Further research will allow us to take into account changes in TREC and KREC indicators in dynamics and use the prognostic value of these changes in the treatment of ovarian cancer. Threshold levels of TREC (13.23 copies / 105 cells) and KREC (251.04 copies / 105 cells) were detected, below which disease progression was observed.

Background. Interleukin (IL) 6 is a potent proinflammatory pleiotropic cytokine and is a key factor in the immune escape of malignant cells. IL-8 (or CXCL8) is a proinflammatory chemokine, high levels of expression of which were observed in various types of cancer.

Aim. To determine the relationship between the level of IL-6 and IL-8 cytokines in the blood serum with the main populations of peripheral blood lymphocytes and its significance for the results of neoadjuvant chemotherapy for triple-negative breast cancer (TN BC).

Materials and methods. All 64 patients received chemotherapy and surgery. The concentrations of IL-6 and IL-8 (ng / ml) in the blood serum and the percentage of the main lymphocyte populations in the peripheral blood (PB) were determined.

Results. The relationship between progression, metastasis and death of patients with higher IL-6 concentrations in the blood serum of patients with TN BC was demonstrated. Before treatment, a positive correlation was found between the IL-6 level and the percentage of HLA-DR, CD3⁺HLA-DR⁺, CD3^–HLA-DR⁺ lymphocytes, which, as previously shown, are negative prognostic factors in TN BC. An increase in the IL-6 level was combined with a decrease in the percentage of CD4⁺ T lymphocytes.

Conclusion. The obtained results are consistent with the position that IL-6 is a negative prognostic factor in patients with BC. The positive relationship between IL-6 and “negative” HLA-DR, CD3⁺HLA-DR⁺, CD3^‒HLA-DR⁺ lymphocyte populations found in the work indicates their interaction in stimulating tumor growth.

Background. Search and development of cancer prevention agents remain relevant. Gallic acid (GA), which has antioxidant, anti-inflammatory, and antiviral activities, is used to treat many diseases. The antitumor properties of GA have been demonstrated mainly in cell cultures. Models of chemically induced carcinogenesis have more possibilities to reveal the anticancer potential of GA.

Aim. To study the antitumor effect of GA at various stages using a model of 1,2-DMH-induced carcinogenesis in mice. To evaluate the effect of GA on the endogenous synthesis of nitric oxide (NO) metabolites.

Materials and methods. CBA line mice (94 females) were divided into 5 groups: Control, GA, 1,2-DMH, GA + 1,2-DMH, 1,2-DMH + GA. The frequency, multiplicity, and morphological characteristics of tumors were determined. NO metabolites were assessed by NO₂– excretion in urine using a spectrophotometric method.

Results. The tumor incidence in animals that received only 1,2-DMH was 100 %. The use of GA before the carcinogen course and throughout the experiment resulted in a moderate decrease in the incidence of intestinal tumors. when GA was administered after the 1,2-DMH course, the effect was stronger and inhibited the growth of all diagnosed tumors. The multiplicity index of tumors in this group was significantly lower compared to that of animals receiving only the carcinogen (p <0.01). Analysis of NO metabolite synthesis showed that GC prevents the excretion of nitrites (NO₂–), contributing to the inhibition of carcinogen-induced tumor development.

Conclusion. The antitumor effect of GA at various stages of 1,2-DMH-induced carcinogenesis was demonstrated. A significant decrease in the frequency and multiplicity of induced and malignant tumors of all localizations was noted in mice that received GA at the stage of carcinogenesis, including the stages of promotion and progression. The inhibitory effects of GA, detected when used both before and after the introduction of the carcinogen, substantiate its effect on all stages of the carcinogenic process. The data obtained expand the possibilities of considering GA as a promising drug in chemoprophylaxis and subsequent use in oncological practice.

Background. Ferroptosis, a non-apoptotic, iron-dependent form of regulated cell death in which membrane phospholipid peroxidation products accumulate within the cell, was discovered relatively recently. Numerous scientific publications in recent years indicate that ferroptosis can lead to the tumor cells death that survive chemotherapy. Therefore, ferroptosis as an alternative pathway for cell death raises hope for new opportunities for the modern anticancer drug therapy development and improvement. 3-Hydroxyquinazoline derivatives as ferroptosis inducers are promising pharmacological substances with pronounced ferroptotic activity.

Aim. To conduct a preliminary assessment of the new domestic derivative of 3-hydroxyquinazoline (OVF-009), antitumor activity, a potential ferroptosis inducer, in mouse tumor growth models administered via two routes of administration (intraperitoneal and oral).

Materials and methods. Original substance OVF-009, excipients (Kolliphor ELP, ethanol 95 %, Kollidon 17 PF, sodium hydroxide, phosphate buffer, etc.); technological methods; immunocompetent mice, tumor models (Lewis lung epidermoid carcinoma, melanoma B-16, cervical cancer CC-5, breast adenocarcinoma Ca-755); biological methods described in the guidelines for drugs antitumor activity preclinical studies. The antitumor effect was assessed by tumor growth inhibition (TGI) of animals treated with OVF-009, compared with animals in the control group.

Results. During the technological stage of the work, an OVF-009 oral dosage form based on corn oil was obtained. For intraperitoneal administration, a previously developed solution based on hydrogenated castor oil was used. The result of the experiments on mice tumor models showed the maximum antitumor effect on melanoma B-16 of 75 % TGI on the 8th day after the end of administration, with Lewis lung epidermoid carcinoma, a high but short-term effect of TGI = 84 % on the 1st day with intraperitoneal administration. with per os administration, the best results were obtained with Ca-755 and CC-5: with Ca-755, a significant antitumor effect was shown with TGI = 7677 % (p <0.05) up to the 8th day after the end of administration; with CC-5, TGI = 73–68 % (p <0.05) was noted from the 8th to the 16th day of observation.

Conclusion. The obtained results on the OVF-009 antitumor activity in mouse tumor models indicate the promise of this original substance continuing in-depth preclinical studies.

Introduction. Ex vivo expansion of natural killer (NK) and natural killer T-cells (NKT) cells is an important element in the generation of chimeric antigen receptor NK and NKT cells. Monoclonal antibodies (mAbs) to CD (cluster of differentiation) 3 and CD28 receptors are most often used for lymphocyte expansion. Other well-studied T-cell mitogens include phytohaemagglutinin-L (L-PHA) and concanavalin A (ConA). A promising but poorly studied approach is in vitro activation of immune cells with the polysaccharide fucosylated chondroitin sulfate (FCS) isolated from the sea cucumber Cucumaria japonica, which is able to activate immune cells and stimulate hematopoiesis.

Aim. To identify the optimal method for NK and NKT cell activation in primary lymphocyte culture. For this purpose, we tested mAbs to CD3 and CD28 receptors, L-PHA, ConA, and a combination of mAbs to CD3 and CD28 receptors and FCS.

Materials and methods. Peripheral blood and leukocyte-platelet concentrate were used as a source of peripheral blood mononuclear cells (PBMC). After isolation of PBMC, they were activated using adsorbed mAbs to CD3 and CD28 receptors, L-PHA, ConA, or a mAbs + FCS combination. Then, lymphocytes were cultured in the presence of IL-2, periodically assessing the increase in the total number of cells, expression of surface markers, and cytotoxic activity.

Results. It was shown that L-PHA best stimulated the expansion of T lymphocytes (CD3⁺CD56^–) and NK cells (CD3^–CD56⁺) relative to other activation modes. Under the influence of ConA, the division of CD3⁺CD4⁺ lymphocytes was significantly activated. when comparing the activation of cells under the influence of MAT relative to L-PHA and ConA, the most pronounced increase in the CD3⁺CD56⁺ population was observed. The addition of FCS during MAT stimulation led to an increase in lymphocyte proliferation.

Conclusion. Thus, among the presented methods of PBMC activation for stimulating the expansion of NK and NKT cells, the most preferable was the MAT + FCS activation method, since it resulted in the greatest increase in the total number of cells with a maximum proportion of CD56⁺ lymphocytes, amounting to 58.9% by the end of the culturing period.

Background. Based on the results of evaluating the mechanical and strength characteristics and studying various aspects of biological activity, a composite material based on polylactide and hydroxyapatite (PLA / HA) is considered a promising component of shape-memory implants for osteoreconstructive surgeries.

Aim. To evaluate the response of laboratory animals to the implantation of PLA / HA-based implant samples, as well as the potential for their use as a platform for the local administration of antibacterial agents.

Materials and methods. Experimental samples were manufactured in the form of surgical staples from a PLA / HA composite material containing 15 % mass fraction of impurities by weight of hydroxyapatite in the form of 90 nm needle-shaped nanoparticles. To study biocompatibility and biodegradation in vivo, the staples were implanted subcutaneously in mice. After 50 days, the samples were removed, their weight changes were assessed, and histological tissue sections in the area of contact with the implants were examined. To explore the potential of using PLA / HA as a platform for local delivery of an antibacterial drug, 35 μg of an amoxicillin / clavulanic acid mixture was applied to the surface of the samples, followed by washing. The loaded samples were then placed on Mueller–Hinton agar seeded with Escherichia coli and Staphylococcus aureus. After 20 hours of incubation, the presence of zones of inhibition of colony formation around the samples and disks was assessed.

Results. The shape memory effect was achieved by heating the samples, resulting in the closure of the initially open fixation clips. Although no significant change in sample weight was observed during their residence in the animals, histological examination of the surrounding tissue revealed signs of their initial biodegradation in vivo. No massive infiltration of tissue in the contact area by inflammatory cells, characteristic of an acute inflammatory response, was detected. However, isolated foreign body giant cells and isolated macrophages, lymphocytes, and neutrophils were observed in some samples. Microbiological studies demonstrated an inhibitory effect on the growth of E. coli and S. aureus colonies around the samples.

Conclusion. The obtained results demonstrated the biocompatibility of PLA / HA with a hydroxyapatite content of 15 % mass fraction of impurities by weight, as its implantation did not induce an acute inflammatory reaction or rejection in experimental animals. Furthermore, it was demonstrated that products made from this material can be used as a platform for the local delivery of antibacterial agents.