In the light of widespread distribution of drug-resistant pathogens, the problem of combatting them becomes critically important in active space exploration and long-term isolated flights. In the conditions of a closed and hermetic spacecraft or lunar base, as well as under the influence of unfavorable factors of space flight: weightlessness, weak magnetic field, ionizing radiation, active changes in the properties of microorganisms occur. In the case of spacecraft and lunar bases, there is a possibility that some surface areas will not be processed and sterilized often enough and the growth and colony formation of microorganisms in the form of biofilms may occur, which is especially dangerous. Rather rapid adaptation of microorganisms to unfavorable factors of space is possible, which will further increase the danger to astronauts. For this reason, it is necessary to start searching for universal and compact means of biological protection for astronauts right now. Metal nanoparticles can be considered as possible means of biological protection due to their antimicrobial properties. However, a wide variety of methods and approaches for describing properties of nanoparticles leads to heterogeneity and inconsistency of the available information regarding their antimicrobial activity, especially in a comparative aspect. In this umbrella review, we summarized the knowledge available in systematic reviews and meta-analyses. The key issue of the review was to evaluate the antimicrobial properties of metal nanoparticles (MNP). The results of the analysis showed the presence of a significant antimicrobial activity in a number of metal nanoparticles, including silver, iron, titanium, zinc, copper, gold, platinum, magnesium, aluminum, bismuth, molybdenum, manganese and cerium. It was found that most of the available works provide insufficient information about the size, shape, activity, and a number of other parameters of nanoparticles, which significantly complicates the analysis, generalization, and use of such knowledge. In view of the revealed incompleteness and heterogeneity of the information presented, we propose a consensus in the form of the minimum necessary information to be reflected in research and review papers devoted to the study of the antimicrobial action of nanoparticles.

Non-invasive radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression can guide patient stratification for EGFR-targeted therapies. The designed ankyrin repeat protein (DARPin) E01, which binds EGFR ectodomain III with sub-nanomolar affinity, is a promising scaffold for single-photon emission computed tomography (SPECT) imaging probes. In the present study, we compared site-specific radioiodination of DARPin E01 using the bifunctional prosthetic group (4-hydroxyphenyl)ethyl maleimide (HPEM) with site-unspecific radioiodination via [123I]I-para-iodobenzoate (PIB). [123I]I-HPEM was conjugated to the C-terminus of DARPin E01 via Glu-Glu-Glu-Cys ([123I]I-E01-E3C-HPEM) or Gly-Gly-Gly-Cys ([123I]I-E01-G3C-HPEM) linkers. Radiolabelling yields were 6 ± 2% and 13 ± 5%, respectively. Size-exclusion purification provided radiochemical purity > 98%. Both HPEM conjugates retained nanomolar EGFR-binding affinity (KD: 3.2 ± 0.6 and 4.8 ± 0.9 nM) and demonstrated EGFR-specific tumour accumulation in A-431 xenografts. Cellular processing was characterised by rapid binding, slow internalisation, and non-residualising behaviour of all variants. Kidney uptake was lower for the site-specifically labelled variants. However, site-specific labelling evidently elevated hepatobiliary excretion and uptake in Na/I-symporter-expressing organs compared to [123I]I-(HE)3-E01-PIB, while linker composition (E3C vs. G3C) did not significantly alter biodistribution. Site-unspecific radioiodination with [123I]I-PIB remains the preferred approach for clinical SPECT imaging of EGFR expression with DARPin E01.

Introduction: This study aimed to investigate a plausible mechanism underlying the potential radiosensitizing activity of lithium L-ascorbate by modelling lithium versus sodium effects in the binding pocket/pore of the sodium-dependent vitamin C transporter SVCT1 in silico. Researchers then conducted in vitro tests to determine if extracellular lithium effectively reduces the accumulation of ascorbate within cells. Methods: SVCT1 protein structures (PDB: 7YTW, 7YTY) were prepared, embedded in lipid membranes, and simulated using GROMACS with CHARMM36 force fields, comparing Na+ and Li+ ion effects on ascorbate transport over 100 ns. Jurkat cells were incubated with ascorbate (100 μM) and Li+ (0.5, 1, 2, and 4 mM) for 24 hours. Intracellular ascorbate levels were measured via stripping voltammetry on a carbon glass electrode. Results: Molecular simulations revealed that Li+ ions delay release from the SVCT1 pocket. It suggested altered ion residence and pore geometry consistent with impaired Na+-coupled ascorbate transport. In vitro experiments showed a significant reduction in intracellular ascorbate concentrations at media Li+ concentrations of 0.5-2 mM. Discussion: We hypothesized that lithium-ion inhibition of SVCT-mediated ascorbate uptake increased extracellular ROS formation. That highlights a potential ion-specific regulatory mechanism in cellular redox homeostasis. Conclusion: These findings support a transport-centered mechanism for lithium-induced radiosensitization, involving inhibition of SVCT1-dependent ascorbate transport. This effect likely promotes extracellular pro-oxidant conditions and oxidative stress, as previously demonstrated.

The objective of the present study was to test the hypothesis that the position of the HYNIC chelator in DARPin G3 variants affects in vivo biodistribution and to select the most effective variant as a 99mTc imaging agent for HER2-expressing tumors. This study evaluated the labelling, affinity, cellular processing, biodistribution, and in vivo targeting specificity of novel N- and C-terminal DARPin G3-HYNIC constructs. In addition, amino acid sequences containing E3C or (G3S)3C at the N- and C-terminus of the protein were used as linkers for HYNIC binding to DARPin G3 to enrich the molecular design of constructs in this study. The results demonstrated that the position of the HYNIC chelating group in DARPin G3 constructs did not affect the binding properties of the target in vitro and in vivo. At the same time, the position of HYNIC was found to strongly influence the biodistribution of labelled DARPin G3 constructs in CD1 mice, showing increased accumulation in the kidneys and decreased levels in the liver, spleen, and lungs when HYNIC was added to the N-terminus of the protein variants. New N- and C-terminal constructs of DARPin G3-HYNIC were generated for HER2 targeting. It is evident that changing the position of the chelator in DARPin G3-HYNIC leads to differences in pharmacokinetic behaviour. The biodistribution of HYNIC variants attached to the N- or C-terminus of DARPin G3 was not significantly altered by different amino acid linkers. Therefore, variants with HYNIC positioned at the N-terminus are more useful for selecting a 99mTc-DARPin G3 imaging tracer. The [99mTc]Tc-HYNIC-C(G3S)3-G3 variant exhibited enhanced biodistribution compared to [99mTc]Tc-HYNIC-CE3-G3, particularly regarding reduced uptake in the liver.

Noninvasive radionuclide imaging of epithelial cell adhesion molecule (EpCAM) expression in lung, ovarian, breast, kidney, and other cancers can stratify patients for EpCAM-targeted therapy. The constructed scaffold proteins, designed ankyrin repeat proteins (DARPins), are highly specific high-affinity probes for radionuclide imaging. A clinical study demonstrated that the anti-EpCAM DARPin [99mTc]Tc-(HE)3-Ec1 showed precise EpCAM imaging at 2, 4, and 6 h after injection in patients with nonsmall cell lung cancer. However, a noticeable accumulation in healthy organs has prompted the development of new Ec1-based agents with improved biodistribution properties. In addition, it would be desirable to substitute a labor-intensive labeling procedure. The purpose of this study was to test the hypothesis that the use of Gly-Gly-Gly-Cys (G3C) or Glu-Glu-Glu-Cys (E3C) peptide chelators placed at the C-terminus of DARPin for labeling with 99mTc (V) could improve the image contrast and biodistribution of Ec1. The radiochemical yield of the new variants exceeded 95%. The labeled proteins specifically bound to human EpCAM-expressing cancer cell lines with affinities of 8-10 nM. The biodistribution of [99mTc]Tc-Ec1-G3C and [99mTc]Tc-Ec1-E3C in mice was compared with the biodistribution of clinically tested [99mTc]Tc-(HE)3-Ec1 in a Nu/j mouse model with SKOV-3 xenografts. The new variants specifically accumulate in human xenografts with EpCAM expression. The accumulation of new variants in healthy organs (liver, salivary glands, spleen, and stomach) was reduced compared to [99mTc]Tc-(HE)3-Ec1. [99mTc]Tc-Ec1-G3C provided the best imaging contrast and is suitable for clinical testing.

Growing interest in cancer radiotherapy has led to the application of nanoparticles as radiosensitizers. Here, we, for the first time, present the results of the radiosensitizing properties of silver nanoparticles (AgNPs) (possessing low toxicity towards human body) against cancer cells under neutron irradiation. Five standard cancer cultures (including glioblastoma, known for its resistance to conventional photon radiation) were used to evaluate the radiosensitizing properties of AgNPs suing MTT test, flow cytometry, and optical fluorescence microscopy. Neutron irradiation was applied in the absorbed dose of 0.5-1.5 Gy with an average neutron energy of 7.5 MeV. AgNPs increased the irradiation efficiency with the radiosensitivity enhancement ratios 1.02-2.32, for glioblastoma with ratios 1.22-1.47. It was revealed that at 1.5 Gy, AgNP-induced cytotoxicity made a significant contribution to the total observed radiosensitizer effect: on average, for five cell types, 29.8 and 96.2 % at the AgNP concentration of 0.2 and 1.6 μg/mL, respectively.

Radionuclide-based molecular imaging modalities are active and developing areas of functional and molecular diagnosis. Among the radionuclides used for SPECT imaging in oncology, 99mTc is a leading candidate for radiolabeling. At present, a sufficient number of complexons for 99mTc have been described; however, the development of effective delivery systems for this isotope to the area of interest is a complex research task. The use of tumor-targeting molecules as carriers for radioactive tracers is an effective strategy that has enabled the development of many novel radiopharmaceuticals for cancer imaging. Background: To date, a number of studies have shown tumorotropicity of tetrapyrrole compounds to tumor tissues, in particular derivatives of natural chlorophyll A. Methods: Purification was performed using solid-phase extraction. Assessment of radiochemical yield and purity was performed via radio-ITLC. The in vitro tumor cell accumulation was assessed using SKOV-3 and A-431 cell lines. Dose-dependent biodistribution was evaluated in Nu/J mice bearing epidermoid carcinoma (A-431) xenografts. Results: In this work, we obtained complexes with 99mTc based on water-soluble carboxylate chlorin e6 derivatives in order to evaluate their potential for use as SPECT radiopharmaceuticals. We performed radiolabelling optimization of a series of the novel chlorins and primary preclinical studies, including an assessment of the effect of their lipophilicity and charge on tumor uptake. Conclusions: Modification of the periphery of the chlorin macrocycle with chelating groups allows for complexing a wide range of metals, including 99mTc, which can be used for targeted delivery of the radionuclide to the area of interest.

IMPORTANCE Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. OBJECTIVE To estimate the worldwide burden of SAH. DESIGN, SETTING, AND PARTICIPANTS Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. EXPOSURES SAH and 14 modifiable risk factors. MAIN OUTCOMES AND MEASURES Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs). RESULTS In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF]=51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF=14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. CONCLUSIONS AND RELEVANCE Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Bone injuries remain a significant challenge, driving the development of new materials and technologies to enhance healing. This study presents a novel approach for incorporating graphene into calcium phosphate (CaP) coatings on titanium alloy (Ti) substrates, with the aim of creating a new generation of materials for bone implant electronics. The stability of the composite coating under physiological conditions, long-term electrical and mechanical durability, and biocompatibility were systematically investigated. We integrated graphene into the CaP coating through the laser processing of diazonium-functionalized graphene films applied to the surface of CaP-coated Ti. The laser treatment induced several processes, including the removal of aryl groups, the formation of conductive pathways, and chemical bonding with the CaP film. As a result, the graphene-CaP nanocomposite demonstrated excellent mechanical durability, withstanding a 2 h sand abrasion test. It also exhibited excellent biocompatibility, as shown by the proliferation of human fibroblast cells for 7 days. The electrical properties remained stable under physiological conditions for 12 weeks, and the material maintained electrochemical stability after 1 million pulse cycles. Furthermore, it withstood the stress of 100,000 bending cycles without compromising electrical performance. This work highlights the versatility of the biocompatible graphene composite and its potential for a range of applications including free-form electronic circuits, electrodes, bending sensors, and electrothermal heaters.

Radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression might permit the selection of patients for EGFR-targeting therapies. Designed ankyrin repeat protein (DARPin) E01 with a high affinity to the ectodomain III of the EGFR is a possible EGFR imaging probe. The goal of this study was to evaluate the potential of radiolabeled DARPin E01 for in vivo imaging of EGFR. DARPin E01 containing the (HE)3-tag was site-specifically labeled with a residualizing 99mTc (using 99mTc]Tc(CO)3). Two methods providing non-residualizing 123I labels, direct electrophilic radioiodination and indirect radioiodination using [123I]I-para-iodobenzoate (PIB), were tested. [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB preserved specific binding to EGFR-expressing cells and affinity in the single-digit nanomolar range. Direct labeling with 123I resulted in a substantial loss of binding. In vitro cellular processing studies showed that both [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB had rapid binding and relatively slow internalization. Evaluation of [99mTc]Tc-(HE)3-E01 biodistribution in normal CD1 mice showed that its hepatic uptake was non-saturable, suggesting that this tracer does not bind to murine EGFR. A side-by-side comparison of biodistribution and tumor targeting of [99mTc]Tc-(HE)3-E01 and [123I]I-(HE)3-E01-PIB was performed in Nu/j mice bearing EGFR-positive A-431 and EGFR-negative Ramos human cancer xenografts. Both radiolabeled DARPins demonstrated EGFR-specific tumor uptake. However, [123I]I-(HE)3-E01-PIB had appreciably lower uptake in normal organs compared to [99mTc]Tc-(HE)3-E01, which provided significantly (p < 0.05) higher tumor-to-organ ratios. Gamma-camera imaging confirmed that [123I]I-(HE)3-E01-PIB demonstrated a higher imaging contrast in preclinical models than [99mTc]Tc-(HE)3-E01. In conclusion, DARPin (HE)3-E01 labeled using a non-residualizing [123I]I-para-iodobenzoate (PIB) label is the preferred radiotracer for in vivo imaging of EGFR expression in cancer.

Background/Objectives: Deep eutectic solvents (DESs) have recently gained attention for their antimicrobial properties, particularly because they target both planktonic bacteria and biofilms. Among these, DESs based on α-hydroxy acids (αHAs) are of interest due to their inherent antibacterial properties and favorable biocompatibility. However, effects of the αHA molecular structure and hydrogen bonding ability within a DES formulation on biological activity has not yet been thoroughly investigated. Methods: This study systematically investigates DESs formed by combining glycolic acid, lactic acid or tartaric acid with either choline chloride or tetraethylammonium chloride. Results: All DESs demonstrate broad-spectrum antibacterial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa and effectively inhibit biofilm formation while exhibiting low cytotoxicity toward 3T3-L1 fibroblasts. Conclusions: DES formation enhances antibacterial efficacy while attenuating cytotoxicity compared to the individual components, thereby decoupling bactericidal activity from toxicity. Physicochemical characterization confirms the formation of a eutectic phase and reveals that biological activity is primarily governed by acidity rather than by the specific αHA structure or eutectic strength. These results provide new insights into structure-function relationships in DESs and establish a design strategy for biocompatible, non-cytotoxic antimicrobial agents.

The use of radiopharmaceuticals for diagnostics in oncology allows for the detection of the disease at an early stage. Among diagnostic radionuclides, 99mTc is a promising isotope that has been used to create several drugs for clinical use. One of the most effective 99mTc chelators is 6-hydrazinylnicotinic acid (HYNIC), which, when combined with various vector molecules, can be used for targeted delivery of radionuclides to tumor tissues. At the same time, it is known that tetrapyrrole macrocycles are capable of selective accumulation in tumors, and thus can be used to target radiopharmaceuticals with 99mTc. In this work, the conjugate of natural chlorin and HYNIC was obtained, and preliminary preclinical studies were carried out on its radiocomplex with 99mTc.

There is currently a demand for anti-adhesive materials that are capable of preventing the formation of intra-abdominal adhesions. In this study, electrospun poly(lactide-co-glycolide) scaffolds were dip-coated in aqueous solutions of polyvinyl alcohol with concentrations of 3 wt.%, 6 wt.% and 9 wt.% to obtain a nontoxic and anti-adhesive biomedical material. The viscosities of the applied 3 wt.%, 6 wt.% and 9 wt.% polyvinyl alcohol solutions were 7.7 mPa∙s, 38.2 mPa∙s and 180.8 mPa∙s, respectively, and increased exponentially. It is shown that increasing the viscosity of the polyvinyl alcohol solution from 6 wt.% to 9 wt.% increases the thickness of the polyvinyl alcohol layer from (3.32 ± 0.97) µm to (8.09 ± 1.43) µm. No pronounced polyvinyl alcohol layer can be observed on samples dip-coated in 3 wt.% PVA solution. Increasing the viscosity of the polyvinyl alcohol solution from 3 wt.% to 9 wt.% increases the mechanical properties of the poly(lactide-co-glycolide) samples by a factor of 1.16–1.45. Cytotoxicity analysis of all samples reveals that none is toxic to 3T3-L1 fibroblast cells. A cell adhesion assay indicates that the anti-adhesion properties increase with increasing viscosity of the polyvinyl alcohol solution and the thickness of the polyvinyl alcohol layer on the poly(lactide-co-glycolide) scaffolds. Fluorescence images of the cells show that as the thickness of the polyvinyl alcohol coating increases, the number of cells decreases, and they do not cover the surface of the samples and form spherical three-dimensional agglomerates. The highest mechanical and anti-adhesion properties are obtained with the poly(lactide-co-glycolide) scaffold sample dip-coated in the 9 wt.% polyvinyl alcohol solution. This is because this sample has the thickest polyvinyl alcohol coating.

Background Ascorbate is used for combination therapy with promising results in clinical trials. The proposed main ascorbate cytotoxic effect is DNA damage induction through excessive oxidative stress. However, the involvement of DNA double-strand breakage (DSB) formation and repair in ascorbate-induced DNA damage remains to be revealed. Methods We here used wild-type cells and cells with knock-outs (KO) of the key non-homologous end-joining (NHEJ) repair proteins DNA-PKcs and XRCC4 and tested 2D and 3D cell viability, growth, DSB (DNA fragmentation and DSB surrogate markers 53BP1 and gamma H2AX), apoptosis, necrosis, and cell cycle in response to ascorbate. Results Ascorbate reduced cell survival and viability in a concentration-dependent manner, with a tendency toward XRCC4 KO cells more sensitivity. Unlike radiation, ascorbate did not produce prompt DSB. However, 24 h after exposure, there was a clear increase in 53BP1 foci in both NHEJ-proficient and KO cells and evident pan-nuclear gamma H2AX response, especially in XRCC4 KO cells, which may indicate nuclear degradation leading to DSB formation over time. Further, ascorbate induced G2/M arrest with a more pronounced effect in XRCC4 KO cells. For higher doses (> 1 mM) we observed a rapid (24 h) necrotic response without activation of apoptosis. The cell line's different response seems to be related to their cell cycle regulation rather than the NHEJ status. These findings provide novel mechanistic insights into DNA damage formation and cellular response to ascorbate. Conclusion Our data suggest that ascorbate does not generate prompt or direct DSBs. Instead, it induces delayed DSBs stemming from nuclear necrotic degradation, driven by cell cycle regulation rather than NHEJ status.

In the present communication, the preparation of deep eutectic solvents (DESs) based on an aqueous solution of lactic acid (LA) and two different quaternary ammonium compounds, choline chloride (ChCl) and tetraethylammonium chloride (TEAC), is proposed for the application as an antibacterial agent. The antibacterial and cytotoxic properties of the DESs obtained were studied and found to be highly effective in inhibiting both Grampositive and Gram-negative bacteria and eradicating bacterial biofilms. Moreover, the DESs obtained exhibited reduced cytotoxicity towards soft tissue cells compared to the aqueous LA solution. The excellent antibacterial properties and low cytotoxicity of the DESs prepared make them a promising candidate for the development of novel antimicrobial agents or antibacterial eutectogels for delivery systems and tissue engineering applications.

Electrospun polytetrafluoroethylene (PTFE)-based artificial pericardium represents a promising material for use in cardiovascular surgery, particularly in cases requiring repeated cardiac interventions. A key factor determining its clinical applicability is its structure. This study presents a comparative evaluation of an artificial pericardium made from polytetrafluoroethylene (PTFE) via electrospinning against a commercial analogue from Gore® (PRECLUDE®). Two morphologies were investigated: fibrous (porosity ~59 ± 2%, fiber diameter 1.25 ± 0.25 µm) and spherical (porosity 34 ± 3%, particle size 3.90 ± 0.75 µm). The commercial sample exhibited a characteristic node-fibril structure with a porosity of 45 ± 3%. The Gore® material was the strongest sample (23.4 ± 2.3 MPa), whereas the electrospun samples demonstrated significantly higher relative elongation (170 ± 20% and 370 ± 10% for the spherical and fibrous samples, respectively, versus 70 ± 20% for the control). In vitro investigation on mice dermal fibroblast culture revealed no cytotoxicity and demonstrated good cell adhesion and proliferation on all investigated materials. Histological analysis after implantation into the rat greater omentum showed that the sample with a spherical structure elicited the least inflammatory response and formed the thinnest fibrous capsule compared to both the fibrous sample and the commercial Gore® material. The results indicate that the electrospinning enables the creation of biocompatible materials for cardiovascular surgery, with the spherical surface morphology being the most promising due to its ability to minimize the inflammatory response in vivo.

Heterodimeric approaches have emerged as a promising method for simultaneously targeting multiple receptors on tumor cells using a single molecule. Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPr) holds the potential to improve the accuracy of prostate cancer diagnosis. The aim of this study was to develop a convenient and simple modular strategy for the creation of heterobivalent (HBV) conjugates targeting PSMA/GRPr receptors. For this purpose, we developed and compared six alternative routes for the stereoselective synthesis of HBV conjugates designed to deliver the chelating agent DOTA to PSMA/GRPr receptors. The comparison of these alternative synthetic pathways took into account such factors as efficiency, complexity, synthesis, and purification details, as well as yields of the target compounds. Optimal conditions for the stereoselective synthesis of HBV ligands to PSMA and GRPr, which could serve as molecular platforms for the targeted delivery of therapeutic or diagnostic agents to these receptors, were revealed. For synthesized HBV ligand 26x and its HBV conjugate with DOTA 27, the complete signal assignment in 1H, 13C, and 15N NMR spectra was achieved using 2D NMR techniques. Based on these data, comprehensive signal assignments were provided for all final compounds in their NMR spectra. The final HBV conjugate 27 was labeled with Lu-177, with yields >99%, and the obtained radiotracer was studied in vitro for its binding specificity, with determining of the KD and Bmax using LNCaP (PSMA+) and PC-3 (GRPr+) cell lines.

Background: Radiosensitivity of tumour cells is a serious problem in the treatment of oncological diseases, which, along with the dama- ging effect of irradiation on healthy tissues, significantly limit the possibilities of radiation therapy; therefore, an important task of modern oncopharmacology is the search and study of new radiosensitizing compounds. The main objective of this study was to investigate the radiosensitising effect of lithium ascorbate in vitro and in vivo under neutron radiation exposure. Material and methods: Evaluation of biological effect in vitro was performed on cell culture of tumour line HCT-116 (human colorectal cancer). To develop a model of tumour growth in vivo, SPF-nude immunodeficient mice (line Nu/j) were used. In vivo xenografts were formed by subcutaneous injection of cell suspension of HCT-116 cell line at a concentration of 2 million cells per 100 µl. The drug was administered to animals before irradiation by intraperitoneal injection in physiological solution at the rate of 2.4 mM/kg of animal weight. Neutron irradiation of cells was performed on cyclotron P-7M, by neutron flux with average energy of 7.5 MeV in the range of absorbed doses of 0.5‒1.5 Gy. Local irradiation of mice tumours was performed once at a dose of 1.5 Gy on a cyclotron with the same flux parameters. Cell viability was assessed by MTT test. Tumour growth parameters were assessed by measuring the sizes of xenografts and calculating the average volume, tumour doubling time and animal life span. Results: Enhancement of cytotoxic effect with combined application of radiation exposure and lithium ascorbate in vitro and in vivo was shown. A dose-dependent decrease in cancer cell viability was found when lithium ascorbate was used at a concentration of 0.1‒0.3 mM in combination with neutron irradiation. It was shown that the average tumour volume decreased by more than 50 % in comparison with the control, the xenografts growth rate slowed down to 72 %, and the median life expectancy of experimental animals increased by 86 % when lithium ascorbate and neutron irradiation were combined. Mechanisms of radiosensitising effect by induction of oxidative stress were proposed. Conclusion: The use of lithium ascorbate results in a more pronounced therapeutic effect of neutron radiation exposure in cellular and animal models of tumour growth.

This study presents the synthesis of new fluorosulfate derivatives of 1,4-naphthoquinone by the SuFEx reaction. Anticancer properties of obtained compounds were studied on PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian cancer), MCF-7 (breast cancer), and Jurkat cell lines. All the studied compounds showed higher cytotoxic effects than Cisplatin. The DFT method was applied to determine the electronic structure characteristics of 1,4-naphthoquinone derivatives associated with cytotoxicity. A method of determination of 2,3-dichloro-1,4-naphthoquinone (NQ), 3-chloro-2-((4-hydroxyphenylamino)-1,4-naphthoquinone (NQ1), and 4-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl fluorosulfate (NQS) in a pharmaceutical substance using an impregnated graphite electrode (IMGE) was developed. The morphology of the IMGE surface was studied using scanning electron microscopy (SEM). The electrochemical behavior of NQ, NQ1, and NQS was studied by cyclic voltammetry (CV) in 0.1 M NaClO4 (96% ethanol solution) at pH 4.0 in a potential range from −1 to +1.2 V. Electrochemical redox mechanisms for the investigated compounds were proposed based on the determining main features of the electrochemical processes. Calibration curves were obtained by linear scan voltammetry in the first derivative mode (LSVFD) with the detection limit (LOD) 7.2 × 10−6 mol·L−1 for NQ, 8 × 10−7 mol·L−1 for NQ1, and 8.6 × 10−8 mol·L−1 for NQS, respectively.

Over the past two decades, targeted therapy has actively developed and, demonstrating impressive clinical results, has gained an increasingly important role in the treatment of cancer. This was facilitated to a large extent by an in-depth understanding of the mechanisms of cancer development, and mainly, the discovery of molecular targets. Despite the fact that targeted therapy can radically change the results of treatment and the prognosis of the disease course in some cancer cases, its effectiveness is sometimes replaced by drug resistance, in others. The authors of the lecture analyzed and systematized therapeutic approaches to addressing a number of important molecular targets that are key for implementing a specific stage in human tumor pathogenesis. These include maintaining chronic proliferative signaling, promoting evasion of cell growth suppressors, inducing angiogenesis, forming immune surveillance, and activating invasion and metastasis. The lecture presented targeted therapy drugs used in the Russian Federation, including antibody-based drugs and small molecule tyrosine kinase inhibitors. It also analyzed mechanisms of molecular interaction between these drugs and their targets, as well as possible factors for developing resistance and ways to overcome these resistance mechanisms.