Antitumor effect of nanophotothermolysis mediated by zinc phthalocyanine particles.

Nanophotothermolysis (NPhT) effect is considered to be an approach for the development of highly selective modalities for anticancer treatment. Herein, we evaluated an antitumor efficacy of NPhT with intravenously injected zinc phthalocyanine particles (ZnPcPs) in murine subcutaneous syngeneic tumor models. In S37 sarcoma-bearing mice a biodistribution of ZnPcPs was studied and the high antitumor efficacy of ZnPcPs-mediated NPhT was shown, including a response of metastatic lesions. The morphological investigation showed the main role of a local NPhT-induced vascular damage in the tumor growth and tumor spread inhibition. Murine tumors of different histological origin were not equally sensitive to the treatment. The results demonstrate a potential of ZnPcPs-mediated NPhT for treatment of surface tumors.

Conjugate of Natural Bacteriochlorin with Doxorubicin for Combined Photodynamic and Chemotherapy.

Chemotherapy is among the main classical approaches to the treatment of oncologic diseases. Its efficiency has been comprehensively proven by clinical examinations; however, the low selectivity of chemotherapeutic agents limits the possibilities of this method, making it necessary to search for new approaches to the therapy of oncologic diseases. Photodynamic therapy is the least invasive method and a very efficient alternative for the treatment of malignant tumors; however, its efficiency depends on the depth of light penetration into the tissue and on the degree of oxygenation of the treatment zone. In this work, a hitherto unknown conjugate of a natural bacteriochlorin derivative and doxorubicin was obtained. In vitro and in vivo studies showed a more pronounced activity of the conjugate against MCF-7 and 4T1 cells and its higher tumorotropicity in animal tumor-bearing animals compared to free anthracycline antibiotic. The suggested conjugate implements the advantages of photodynamic therapy and chemotherapy and has great potential in cancer treatment.

Correction: Yagolovich et al. DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma. Int. J. Mol. Sci. 2022, 23, 12687.

In the original publication [...].

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates.

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors.

N-Heterocyclic Carbenes and Their Metal Complexes Based on Histidine and Histamine Derivatives of Bacteriopurpurinimide for the Combined Chemo- and Photodynamic Therapy of Cancer.

Photodynamic therapy (PDT) is currently regarded as a promising method for the treatment of oncological diseases. However, it involves a number of limitations related to the specific features of the method and the specific characteristics of photosensitizer molecules, including tumor hypoxia, small depth of light penetration into the tumor tissue, and low accumulation sensitivity. These drawbacks can be overcome by combining PDT with other treatment methods, for example, chemotherapy. In this work, we were the first to obtain agents that contain bacteriopurpurinimide as a photodynamic subunit and complexes of gold(I) that implement the chemotherapy effect. To bind the latter agents, N-heterocyclic carbenes (NHC) based on histidine and histamine were obtained. We considered alternative techniques for synthesizing the target conjugates and selected an optimal one that enabled the production of preparative amounts for biological assays. In vitro studies showed that all the compounds obtained exhibited high photoinduced activity. The C-donor Au(I) complexes exhibited the maximum specific activity at longer incubation times compared to the other derivatives, both under exposure to light and without irradiation. In in vivo studies, the presence of histamine in the NHC-derivative of dipropoxy-BPI (7b) had no significant effect on its antitumor action, whereas the Au(I) metal complex of histamine NHC-derivative with BPI (8b) resulted in enhanced antitumor activity and in an increased number of remissions after photodynamic treatment.

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma.

TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of tumor cells to TRAIL. In the current study, we improved the antitumor activity of DR5-B by fusion with a tumor-homing iRGD peptide, which is known to enhance the drug penetration into tumor tissues. The obtained bispecific fusion protein DR5-B-iRGD exhibited dual affinity for DR5 and integrin αvß3 receptors. DR5-B-iRGD penetrated into U-87 tumor spheroids faster than DR5-B and demonstrated an enhanced antitumor effect in human glioblastoma cell lines T98G and U-87, as well as in primary patient-derived glioblastoma neurospheres in vitro. Additionally, DR5-B-iRGD was highly effective in a xenograft mouse model of the U-87 human glioblastoma cell line in vivo. We suggest that DR5-B-iRGD may become a promising candidate for targeted therapy for glioblastoma.

Independent evaluation of the accuracy of 5 artificial intelligence software for detecting lung nodules on chest X-rays.

Background: The integration of artificial intelligence (AI) into medicine is growing, with some experts predicting its standalone use soon. However, skepticism remains due to limited positive outcomes from independent validations. This research evaluates AI software's effectiveness in analyzing chest X-rays (CXR) to identify lung nodules, a possible lung cancer indicator. Methods: This retrospective study analyzed 7,670,212 record pairs from radiological exams conducted between 2020 and 2022 during the Moscow Computer Vision Experiment, focusing on CXR and computed tomography (CT) scans. All images were acquired during clinical routine. The final dataset comprised 100 CXR images (50 with lung nodules, 50 without), selected consecutively and based on inclusion and exclusion criteria, to evaluate the performance of all five AI-based solutions, participating in the Moscow Computer Vision Experiment and analyzing CXR. The evaluation was performed in 3 stages. In the first stage, the probability of a nodule in the lung obtained from AI services was compared with the Ground Truth (1-there is a nodule, 0-there is no nodule). In the second stage, 3 radiologists evaluated the segmentation of nodules performed by the AI services (1-nodule correctly segmented, 0-nodule incorrectly segmented or not segmented at all). In the third stage, the same radiologists additionally evaluated the classification of the nodules (1-nodule correctly segmented and classified, 0-all other cases). The results obtained in stages 2 and 3 were compared with Ground Truth, which was common to all three stages. For each stage, diagnostic accuracy metrics were calculated for each AI service. Results: Three software solutions (Celsus, Lunit INSIGHT CXR, and qXR) demonstrated diagnostic metrics that matched or surpassed the vendor specifications, and achieved the highest area under the receiver operating characteristic curve (AUC) of 0.956 [95% confidence interval (CI): 0.918 to 0.994]. However, when evaluated by three radiologists for accurate nodule segmentation and classification, all solutions performed below the vendor-declared metrics, with the highest AUC reaching 0.812 (95% CI: 0.744 to 0.879). Meanwhile, all AI services demonstrated 100% specificity at stages 2 and 3 of the study. Conclusions: To ensure the reliability and applicability of AI-based software, it is crucial to validate performance metrics using high-quality datasets and engage radiologists in the evaluation process. Developers are recommended to improve the accuracy of the underlying models before allowing the standalone use of the software for lung nodule detection. The dataset created during the study may be accessed at https://mosmed.ai/datasets/mosmeddatargogksnalichiemiotsutstviemlegochnihuzlovtipvii/.

Radiosensitizing effects of heparinized magnetic iron oxide nanoparticles in colon cancer.

The combination of radiation treatment and chemotherapy is currently the standard for management of cancer patients. However, safe doses do not often provide effective therapy, then pre-treated patients are forced to repeat treatment with often already increased tumor resistance to drugs and irradiation. One of the solutions we suggest is to improve primary course of radiation treatment via enhancing radiosensitivity of tumors by magnetic-guided iron oxide nanoparticles (magnetite). We obtained spherical heparinized iron oxide nanoparticles (hIONPs, ∼20 nm), characterized it by TEM, Infrared spectroscopy and DLS. Then hIONPs cytotoxicity was assessed for colon cancer cells (XTT assay) and cellular uptake of nanoparticles was analyzed with X-ray fluorescence. Combination of ionizing radiation (IR) and hIONPs in vitro caused an increase of G2/M arrest of cell cycle, mitotic errors and decrease in survival (compared with samples exposed to IR and hIONPs separately). The promising results were shown for magnetic-guided hIONPs in CT26-grafted BALB/C mice: the combination of intravenously administrated hIONPs and IR showed 20,8% T/C ratio (related to non-treated mice), while single radiation had no shown significant decrease in tumor growth (72,4%). Non-guided by magnets hIONPs with IR showed 57,9% of T/C. This indicates that ultra-small size and biocompatible molecule are not the key to successful nano-drug design, in each case, delivery technologies need to be improved when transferred to in vivo model.

Dual targeting of DR5 and VEGFR2 molecular pathways by multivalent fusion protein significantly suppresses tumor growth and angiogenesis.

Destroying tumor vasculature is a relevant therapeutic strategy due to its involvement in tumor progression. However, adaptive resistance to approved antiangiogenic drugs targeting VEGF/VEGFR pathway requires the recruitment of additional targets. In this aspect, targeting TRAIL pathway is promising as it is an important component of the immune system involved in tumor immunosurveillance. For dual targeting of malignant cells and tumor vascular microenvironment, we designed a multivalent fusion protein SRH-DR5-B-iRGD with antiangiogenic VEGFR2-specific peptide SRH at the N-terminus and a tumor-targeting and -penetrating peptide iRGD at the C-terminus of receptor-selective TRAIL variant DR5-B. SRH-DR5-B-iRGD obtained high affinity for DR5, VEGFR2 and αvß3 integrin in nanomolar range. Fusion of DR5-B with effector peptides accelerated DR5 receptor internalization rate upon ligand binding. Antitumor efficacy was evaluated in vitro in human tumor cell lines and primary patient-derived glioblastoma neurospheres, and in vivo in xenograft mouse model of human glioblastoma. Multivalent binding of SRH-DR5-B-iRGD fusion efficiently stimulated DR5-mediated tumor cell death via caspase-dependent mechanism, suppressed xenograft tumor growth by >80 %, doubled the lifespan of xenograft animals, and inhibited tumor vascularization. Therefore, targeting DR5 and VEGFR2 molecular pathways with SRH-DR5-B-iRGD protein may provide a novel therapeutic approach for treatment of solid tumors.

Measurements of dichroic bow-tie antenna arrays with integrated cold-electron bolometers using YBCO oscillators.

We consider properties of dichroic antenna arrays on a silicon substrate with integrated cold-electron bolometers to detect radiation at frequencies of 210 and 240 GHz. This frequency range is widely used in cosmic microwave background experiments in space, balloon, and ground-based missions such as BICEP Array, LSPE, LiteBIRD, QUBIC, Simons Observatory, and AliCPT. As a direct radiation detector, we use cold-electron bolometers, which have high sensitivity and a wide operating frequency range, as well as immunity to spurious cosmic rays. Their other advantages are the compact size of the order of a few micrometers and the effect of direct electron cooling, which can improve sensitivity in typical closed-loop cycle 3He cryostats for space applications. We study a novel concept of cold-electron bolometers with two SIN tunnel junctions and one SN contact. The amplitude-frequency characteristics measured with YBCO Josephson Junction oscillators show narrow peaks at 205 GHz for the 210 GHz array and at 225 GHz for the 240 GHz array; the separation of these two frequency bands is clearly visible. The noise equivalent power level at an operating point in the current bias mode is 5 × 10-16 W/√Hz.

Advantages of Long-Wavelength Photosensitizer meso-Tetra(3-pyridyl) Bacteriochlorin in the Therapy of Bulky Tumors.

This research presents a novel synthetic photosensitizer for the photodynamic therapy (PDT) of malignant tumors: meso-tetra(3-pyridyl) bacteriochlorin, which absorbs at 747 nm (in the long-wavelength region of the spectrum) and is stable when stored in the dark. H2Py4BC demonstrates pronounced photoinduced activity in vitro against tumor cells of various geneses (IC50 varies from 21 to 68 nM for HEp2, EJ, S37, CT26, and LLC cultured cells) and in vivo provides pronounced antitumor efficacy in the treatment of mice bearing small or large S37, Colo26, or LLC metastatic tumors, as well as in the treatment of rats bearing RS-1 liver cholangioma. As a result, total regression of primary tumor nodules and cure of 40 to 100% of the animals was proven by the experiment criteria, MRI, and histological analysis. Meso-tetra(3-pyridyl) bacteriochlorin quickly penetrates and accumulates in the tumor tissue and internal organs of mice, and after 24 h, 80% of the dye is excreted from the skin in addition to 87-92% from the liver, kidneys, and spleen.

Investigation of Hafnium Thin Films for Design of TES Microcalorimeters.

Hafnium is a superconductor with a transition temperature slightly above 100 mK. This makes it attractive for such applications as microcalorimeters with high energy resolution. We report the superconducting properties of Hf films of thicknesses ranging from 60 to 115 nm, deposited on Si and Al2O3 substrates by electron beam evaporation. Besides that, we fabricated and measured combinations of hafnium with thin layers of normal metals, decreasing the critical temperature by the proximity effect. The critical temperature of the studied films varied from 56 to 302 mK. We have observed a significant change in the critical temperature of some films over time, which we propose to prevent by covering hafnium films with a thin layer of titanium.

Cold-adapted SARS-CoV-2 variants with different temperature sensitivity exhibit an attenuated phenotype and confer protective immunity.

As novel SARS-CoV-2 Variants of Concern emerge, the efficacy of existing vaccines against COVID-19 is declining. A possible solution to this problem lies in the development of a live attenuated vaccine potentially able of providing cross-protective activity against a wide range of SARS-CoV-2 antigenic variants. Cold-adapted (ca) SARS-CoV-2 variants, Dubrovka-ca-B4 (D-B4) and Dubrovka-ca-D2 (D-D2), were obtained after long-term passaging of the Dubrovka (D) strain in Vero cells at reduced temperatures. Virulence, immunogenicity, and protective activity of SARS-CoV-2 variants were evaluated in experiments on intranasal infection of Syrian golden hamsters (Mesocricetus auratus). In animal model infecting with ca variants, the absence of body weight loss, the significantly lower viral titer and viral RNA concentration in animal tissues, the less pronounced inflammatory lesions in animal lungs as compared with the D strain indicated the reduced virulence of the virus variant. Single intranasal immunization with D-B4 and D-D2 variants induced the production of neutralizing antibodies in hamsters and protected them from infection with the D strain and the development of severe pneumonia. It was shown that for ca SARS-CoV-2 variants, the temperature-sensitive (ts) phenotype was not obligate for virulence reduction. Indeed, the D-B4 variant, which did not possess the ts phenotype but had lost the ability to infect human lung cells Calu-3, exhibited reduced virulence in hamsters. Consequently, the potential phenotypic markers of attenuation of ca SARS-CoV-2 variants are the ca phenotype, the ts phenotype, and the change in species specificity of the virus. This study demonstrates the great potential of SARS-CoV-2 cold adaptation as a strategy to develop a live attenuated COVID-19 vaccine.

Drastic suppression of noise-induced errors in underdamped long Josephson junctions.

The fluctuational propagation of solitons (magnetic fluxons) in long Josephson junctions is studied both numerically and analytically. It is demonstrated that operation in conditions where solitons are subjected to Lorentz contraction for a significant part of the junctions length leads to drastic suppression of thermal jitter at the output junction end. Specifically, for large-to-critical damping and small values of bias current, the physically obvious dependence of the jitter versus length σ~√L is confirmed, while for small damping starting from the experimentally relevant α=0.1 and below, strong deviation from σ~√L is observed, up to nearly complete independence of the jitter versus length, which is supported by the obtained theory.

Numerical modeling of a multi-frequency receiving system based on an array of dipole antennas for LSPE-SWIPE.

Here we present the results of a numerical modeling of mode composition in the constriction of the Large Scale Polarization Explorer-Short-Wavelength Instrument for the Polarization Explorer (LSPE-SWIPE) back-to-back horn. These results are used for calculating the frequency response of arrays of planar dipole antennas with cold-electron bolometers for 145, 210, and 240 GHz frequencies. For the main frequency channel (i.e., 145 GHz) we have a 45 GHz bandwidth. For the auxiliary frequency channels (i.e., 210 and 240 GHz) placed on the same substrate, we have bandwidths of 26 and 38 GHz, respectively. We performed some optimizations for cold-electron bolometers to achieve a photon noise-equivalent power of 1.1 × 10-16 W/Hz1/2. This was achieved by replacing one of two superconductor-insulator-normal tunnel junctions with a superconductor-normal metal contact.

Efficiency of electron cooling in cold-electron bolometers with traps.

Electron on-chip cooling from the base temperature of 300 mK is very important for highly sensitive detectors operating in space due to problems of dilution fridges at low gravity. Electron cooling is also important for ground-based telescopes equipped with 3He cryostats being able to function at any operating angle. This work is aimed at the investigation of electron cooling in the low-temperature range. New samples of cold-electron bolometers with traps and hybrid superconducting/ferromagnetic absorbers have shown a temperature reduction of the electrons in the refrigerator junctions from 300 to 82 mK, from 200 to 33 mK, and from 100 to 25 mK in the idle regime without optical power load. The electron temperature was determined by solving heat balance equations with account of the leakage current, sixth power of temperature in the whole temperature range, and the Andreev current using numerical methods and an automatic fit algorithm.

Approaching microwave photon sensitivity with Al Josephson junctions.

Here, we experimentally test the applicability of an aluminium Josephson junction of a few micrometers size as a single photon counter in the microwave frequency range. We have measured the switching from the superconducting to the resistive state through the absorption of 10 GHz photons. The dependence of the switching probability on the signal power suggests that the switching is initiated by the simultaneous absorption of three and more photons, with a dark count time above 0.01 s.

A New Glutathione-Cleavable Theranostic for Photodynamic Therapy Based on Bacteriochlorin e and Styrylnaphthalimide Derivatives.

Herein, we report a new conjugate BChl-S-S-NI based on the second-generation photosensitizer bacteriochlorin e6 (BChl) and a 4-styrylnaphthalimide fluorophore (NI), which is cleaved into individual functional fragments in the intracellular medium. The chromophores in the conjugate were cross-linked by click chemistry via a bis(azidoethyl)disulfide bridge which is reductively cleaved by the intracellular enzyme glutathione (GSH). A photophysical investigation of the conjugate in solution by using optical spectroscopy revealed that the energy transfer process is realized with high efficiency in the conjugated system, leading to the quenching of the emission of the fluorophore fragment. It was shown that the conjugate is cleaved by GSH in solution, which eliminates the possibility of energy transfer and restores the fluorescence of 4-styrylnaphthalimide. The photoinduced activity of the conjugate and its imaging properties were investigated on the mouse soft tissue sarcoma cell line S37. Phototoxicity studies in vitro show that the BChl-S-S-NI conjugate has insignificant dark cytotoxicity in the concentration range from 15 to 20,000 nM. At the same time, upon photoexcitation, it exhibits high photoinduced activity.

Nonmonotonous temperature dependence of Shapiro steps in YBCO grain boundary junctions.

The amplitudes of the first Shapiro steps for an external signal with frequencies of 72 and 265 GHz are measured as function of the temperature from 20 to 80 K for a 6 µm Josephson grain boundary junction fabricated by YBaCuO film deposition on an yttria-stabilized zirconia bicrystal substrate. Non-monotonic dependences of step heights for different external signal frequencies were found in the limit of a weak driving signal, with the maxima occurring at different points as function of the temperature. The step heights are in agreement with the calculations based on the resistively-capacitively shunted junction model and Bessel theory. The emergence of the receiving optima is explained by the mutual influence of the varying critical current and the characteristic frequency.

Photodiagnosis and photodynamic effects of bacteriochlorin-naphthalimide conjugates on tumor cells and mouse model.

Photo-induced cytotoxicity and antitumor activity of a series of dual function agents for photodynamic therapy (PDT) and fluorescent imaging based on bacteriochlorin photosensitizer conjugated with various naphthalimide fluorophores was studied in vitro using murine tumor cells of S37 sarcoma and in vivo on mice bearing murine S37 sarcoma. Upon irradiation at the absorption maximum of the photosensitizer, the activity of conjugates was as high as in the case of individual bacteriochlorin, while an additional excitation of the naphthalimide fragment led to an increase in the PDT efficacy due to resonance energy transfer from the fluorophore to photosensitizer. The fluorescence contrast and specific cytotoxic activity measurements indicate that the conjugate of bacteriochlorin with 3,4-dimethoxestyrene-substituted naphthalimide is the most promising agent for the application as theranostic in PDT.