Moskalensky, Alexander Efimovich

Panfilov M.A., Starodubtseva E.S., Karogodina T.Y., Vorob’ev A.Y., Moskalensky A.E.

Engineered light-sensitive molecules offer a sophisticated toolkit for the manipulation of biological systems with both spatial and temporal precision. Notably, artificial “caged” compounds can activate specific receptors solely in response to light exposure. However, the uncaging process can lead to the formation of potentially harmful byproducts. For example, the photochemical release of adrenaline (epinephrine) is accompanied by the formation of adrenochrome, which has neuro- and cardiotoxic effects. To investigate this effect in detail, we synthesized and compared two “caged” epinephrine analogs. The first was a classical compound featuring an ortho-nitrobenzyl protecting group attached to the amino group of epinephrine. The second analog retained the ortho-nitrobenzyl group but included an additional carbamate linker. The photolysis of both compounds was conducted under identical conditions, and the resulting products were analyzed using UV–Vis spectroscopy, chromatography, and NMR techniques. Surprisingly, while the classical compound led to the formation of adrenochrome, the carbamate-type caged epinephrine did not produce this byproduct, resulting in the clean release of the active substance. Subsequently, we assessed the novel compound in an in vitro platelet activation assay. The results demonstrated that the uncaging of epinephrine significantly enhances platelet activation, making it a valuable tool for advanced signaling studies.

Virts N.A., Karogodina T.Y., Panfilov M.A., Vorob'ev A.Y., Moskalensky A.E.

ABSTRACTLocal therapeutic action and targeted drug release are promising approaches compared to traditional systemic drug administration. This is especially relevant for nitric oxide (NO), as its effects change dramatically depending on concentration and cellular context. Materials capable of releasing NO in deep tissues in a controlled manner might open new therapeutic opportunities. Light‐sensitive NO donors represent a fascinating class of compounds with significant potential for precise and controlled NO release. However, most of them are sensitive to visible light, with only a few examples absorbing in a near‐infrared therapeutic window. Here, we present the proof‐of‐concept of soft implants consisting of the photon upconverting core and the outer shell loaded with visible‐light triggered NO donor. The separation into two compartments results in efficient energy harvesting by the dye and effective NO release under 980 nm infrared irradiation. Such implants could be used in smart therapies implying well‐controlled and localized NO release.

Starodubtseva E.S., Karogodina T.Y., Panfilov M.A., Sheven D.G., Selyutina O.Y., Vorob’ev A.Y., Moskalensky A.E.

Control of biological activity with light is a fascinating idea. “Caged” compounds, molecules modified with photolabile protecting group, are one of the instruments for this purpose. Adrenergic receptors are essential regulators of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. These receptors are largely used as pharmacologic targets. Photolabile “caged” analogs of adrenergic receptor agonists has been reported more than 30 years ago. We report that the photolysis of epinephrine analogs, apart from liberation of the epinephrine, is accompanied by a formation of significant amount of adrenochrome, a compound with neuro- and cardiotoxic effect.

Starodubtseva E.S., Karogodina T.Y., Moskalensky A.E.

Disorders of hemostasis resulting in bleeding or thrombosis are leading cause of mortality in the world. Blood platelets are main players in hemostasis, providing the primary response to the vessel wall injury. In this case, they rapidly switch to the activated state in reaction to the exposed chemical substances such as ADP, collagen and thrombin. Molecular mechanisms of platelet activation are known, and detailed computational models are available. However, they are too complicated for large-scale problems (e.g. simulation of the thrombus growth) where less detailed models are required, which still should take into account the variation of agonist concentration and heterogeneity of platelets. In this paper, we present a simple model of the platelet population response to a spatially inhomogeneous stimulus. First, computational nodes modeling platelets are placed randomly in space. Each platelet is assigned the specific threshold for agonist, which determines whether it becomes activated at a given time. The distribution of the threshold value in a population is assumed to be log-normal. The model was validated against experimental data in a specially designed system, where the photorelease of ADP was caused by localized laser stimulus. In this system, a concentration of ADP obeys 2-dimensional Gaussian distribution which broadens due to the diffusion. The response of platelets to the point-like source of ADP is successfully described by the presented model. Our results advance the understanding of platelet function during hemostatic response. The simulation approach can be incorporated into larger computational models of thrombus formation.

Virts N.A., Karogodina T.Y., Panfilov M.A., Vorob’ev A.Y., Moskalensky A.E.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Light-controllable NO releasers show promise in the development of smart therapies. Here, we present a novel biocompatible material based on polydimethylsiloxane (PDMS) doped with BODIPY derivatives containing an N-nitroso moiety that is capable of the photoinduced generation of NO. We study the green-light-induced NO-release properties with the following three methods: electrochemical gas-phase sensor, liquid-phase sensor, and the Griess assay. Prolonged release of NO from the polymer films after short irradiation by narrow-band LED light sources and a laser beam is demonstrated. Importantly, this was accompanied by no or little release of the parent compound (BODIPY-based photodonor). Silicone films with the capability of controllable and clean NO release can potentially be used as a highly portable NO delivery system for different therapeutic applications.

Panfilov M.A., Karogodina T.Y., Sibiryakova A.A., Tretyakova I.S., Vorob'ev A.Y., Moskalensky A.E.

AbstractNitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short lifetime in physiological conditions and local action impede direct application in medicine because highly targeted NO‐delivery systems are required. Light‐controllable NO releasers are promising for the development of smart therapies. Here we present simply prepared meso‐aminomethyl BODIPY (4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene) derivatives containing N‐nitroso moiety, which show the photoinduced generation of NO in a solution. These compounds can additionally generate singlet oxygen, and NO/1O2 generation efficiency can be tuned by substituents. As an example of NO‐mediated effect, we demonstrate light‐dependent inhibition of platelet activation in vitro. The presented compounds could serve as the basis for the development of novel hybrid therapeutic methods.

Litunenko D.N., Moskalensky A.E.

AbstractCell cultures are widely used in scientific research, biomedicine, and industry. When culturing, it is important to maintain certain conditions, including the concentration of cells. Monitoring of the culture growth and cell counting is an urgent task for the optimization of technological processes. Most existing methods require sampling from a culture flask. This procedure is time‐consuming and associated with the risks of contamination. We present a device able to monitor the growth of cells number in a suspension noninvasively. The device uses a laser beam that pass through the culture flask and measures the intensity of scattered light as a function of coordinate along the beam. This optical scheme allows one to obtain accurate results for both high‐ and low‐scattering samples. We constructed the wireless portable prototype for monitoring of cell culture growth directly in the incubator and demonstrated the applicability of the device for Jurkat cells and Escherichia coli bacteria.

Litunenko D.N., Moskalensky A.E.

Panfilov M., Karogodina T., Sibiryakova A., Tretyakova I., Vorob’ev A., Moskalensky A.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short lifetime in physiological conditions and local action impede direct application in medicine because highly targeted NO-delivery systems are required. Light-controllable NO releasers are promising for the development of smart therapies. Here we present simply prepared meso-aminomethyl BODIPY derivatives containing N-nitroso moiety, which show the photoinduced generation of NO in a solution. These compounds can additionally generate singlet oxygen, and NO/1O2 generation efficiency can be tuned by substituents. As an example of NO-mediated effect, we demonstrate light-dependent inhibition of platelet activation in vitro. The presented compounds could serve as the basis for the development of novel hybrid therapeutic methods.

Zhermolenko E.O., Karogodina T.Y., Vorobev A.Y., Panfilov M.A., Moskalensky A.E.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short half-life and local action impede direct application in medical practice. Light-controllable NO releasers are promising for the development of smart therapies. Here, we present novel aza-BODIPY derivative containing N-nitroso moiety, which shows efficient and reversible release of NO under red light. Using this molecule, we demonstrate a system for precise management of NO concentration in aqueous solution in vitro using the feedback loop with optical control. Our results could serve as the basis for the development of novel therapeutic methods.

Panfilov M., Karogodina T., Sibiryakova A., Tretyakova I., Vorob’ev A., Moskalensky A.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short half-life and local action impede direct application in medicine because highly targeted NO-delivery systems are required. Light-controllable NO releasers are promising for the development of smart therapies. Here we present novel simply prepared meso-aminomethyl BODIPY dyes containing N-Nitroso moiety and show the photoinduced generation of NO in a solution. As an example of NO-mediated effects, we demonstrate efficient light-dependent inhibition of platelet activation in vitro. We also show that some compounds could additionally generate singlet oxygen, which is promising for the photodynamic therapy. The presented compounds could serve as the basis for the development of novel hybrid therapeutic methods.

Zhermolenko E.O., Karogodina T.Y., Vorobev A.Y., Panfilov M.A., Moskalensky A.E.

AbstractNitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short half-life and local action impede direct application in medical practice. Light-controllable NO releasers are promising for the development of smart therapies. Here we present novel aza-BODIPY derivative containingN-nitroso moiety, which shows efficient and reversible release of NO under red light. Using this molecule, we demonstrate a system for precise management of NO concentration in aqueous solutionin vitrousing the feedback loop with optical control. Our results could serve as the basis for the development of novel therapeutic methods.

Litunenko D.N., Karogodina T.Y., Vorob’ev A.Y., Moskalensky A.E.

Panfilov M.A., Karogodina T.Y., Songyin Y., Karmatskih O.Y., Vorob'ev A.Y., Tretyakova I.S., Glebov E.M., Moskalensky A.E.

During recent years, the BODIPY core became a popular scaffold for designing of dyes with desirable properties. In this paper, we extend the library of possible modification of BODIPYs, presenting experimental data for a new family meso -substituted with nitrophenyl groups. We also present quantum chemical calculations, which complement the experimental data and give additional insight in the underlying photochemical and photophysical processes. Optical properties of novel compounds are characterized. It is shown that the fluorescence quantum yield and the efficiency of singlet oxygen generation differs by two orders of magnitude across the family. In aqueous solution, red-shifted fluorescence emission band is detected, corresponding to aggregates. This band has shorter decay time and wide excitation spectrum. We show that photolysis is not accompanied by the release of nitric oxide (NO) which was observed earlier for some dyes with nitrophenyl substituents. The experimental data presented in this paper may be useful for further designing of BODIPY dyes and NO photodonors. • We describe a new family of BODIPY dyes with sterically-hindered nitrophenyls in meso-position. • Optical properties of novel compounds are characterized, including the fluorescence quantum yieldand photoinduced singlet oxygen luminescence. • Drastically different results are obtained for molecules with only small changes in substituents. • The influence of molecular structure is explained with quantum chemical calculations.

Chernova D.N., Moskalensky A.E.

Monitoring of cell culture growth is of interest for many industrial and scientific areas. We present a device that non-invasively evaluates the cell concentration in a culture flask based on the light scattering measurements.

Nelliat M., Mohan G., Shastry S., Lukose J., Matham M.V., Chidangil S.

Marcano Olaizola A.

We report on the phosphorescence of singlet oxygen photogenerated through a stimulated Raman process. Nanosecond radiation in the green spectral region focused on hexane and carbon tetrachloride induces a Raman transition of the dissolved solvent oxygen molecules towards the singlet oxygen state, producing a Stokes signal in the near-infrared. The excited oxygen relaxes to the ground, emitting an infrared photon at 1272 nm. While the Stokes signal’s wavelength changes with the light’s wavelength, the wavelength of the phosphorescent photon remains unaltered. The result confirms previous reports on the stimulated Raman excitation of singlet oxygen.

Han D., Tarafder A., Griffith B.P., Wu Z.J.

The power-law model, originally developed for shear-induced hemolysis, has been used to predict shear-induced platelet activation and receptor shedding. However, its empirical nature lacks mechanistic explanations and violates physical reality by not imposing an upper limit, often leading to inaccuracies. Recent studies suggest that the mechanical pulling of platelet GPIb-IX complex triggers the unfolding of its mechanosensitive domain, a crucial process to platelet activation, which can be explained by Bell’s model of bond unbinding under force. Motivated by these findings, we propose a novel mathematical model for shear-induced platelet activation (P-selectin) and shear-induced platelet receptor (glycoprotein Ibα [GPIbα], GPVI, and GPIIb/IIIa) shedding based on the principle of bond unbinding. The model was examined using experimental data from previous studies in which blood samples were exposed to different combinations of constant shear stress and exposure time. The new model demonstrated an excellent fit with experimental data with an overall coefficient of determination R 2 >0.8, mapping the trends in platelet activation and receptor shedding (except for GPIIb/IIIa) across a range of shear conditions. This new model not only addresses the intrinsic upper bound error in the power-law model but also provides a theoretical foundation into blood damage under shear stress.

Zhou J., Mei L., Yu M., Ma X., Hou D., Yin Z., Liu X., Ding Y., Yang K., Xiao R., Yuan X., Weng Y., Long M., Hu T., Hou J., et. al.

Abstract Imaging flow cytometry (IFC) combines the imaging capabilities of microscopy with the high throughput of flow cytometry, offering a promising solution for high-precision and high-throughput cell analysis in fields such as biomedicine, green energy, and environmental monitoring. However, due to limitations in imaging framerate and real-time data processing, the real-time throughput of existing IFC systems has been restricted to approximately 1000-10,000 events per second (eps), which is insufficient for large-scale cell analysis. In this work, we demonstrate IFC with real-time throughput exceeding 1,000,000 eps by integrating optical time-stretch (OTS) imaging, microfluidic-based cell manipulation, and online image processing. Cells flowing at speeds up to 15 m/s are clearly imaged with a spatial resolution of 780 nm, and images of each individual cell are captured, stored, and analyzed. The capabilities and performance of our system are validated through the identification of malignancies in clinical colorectal samples. This work sets a new record for throughput in imaging flow cytometry, and we believe it has the potential to revolutionize cell analysis by enabling highly efficient, accurate, and intelligent measurement.

Panfilov M.A., Starodubtseva E.S., Karogodina T.Y., Vorob’ev A.Y., Moskalensky A.E.

Engineered light-sensitive molecules offer a sophisticated toolkit for the manipulation of biological systems with both spatial and temporal precision. Notably, artificial “caged” compounds can activate specific receptors solely in response to light exposure. However, the uncaging process can lead to the formation of potentially harmful byproducts. For example, the photochemical release of adrenaline (epinephrine) is accompanied by the formation of adrenochrome, which has neuro- and cardiotoxic effects. To investigate this effect in detail, we synthesized and compared two “caged” epinephrine analogs. The first was a classical compound featuring an ortho-nitrobenzyl protecting group attached to the amino group of epinephrine. The second analog retained the ortho-nitrobenzyl group but included an additional carbamate linker. The photolysis of both compounds was conducted under identical conditions, and the resulting products were analyzed using UV–Vis spectroscopy, chromatography, and NMR techniques. Surprisingly, while the classical compound led to the formation of adrenochrome, the carbamate-type caged epinephrine did not produce this byproduct, resulting in the clean release of the active substance. Subsequently, we assessed the novel compound in an in vitro platelet activation assay. The results demonstrated that the uncaging of epinephrine significantly enhances platelet activation, making it a valuable tool for advanced signaling studies.

Specht A., Klimezak M., Cambridge S.

AbstractNew concepts to treat eye diseases have emerged that elegantly combine unnatural light exposure with chemical biology approaches to achieve superior cellular specificity and, as a result, improvement of visual function. Historically, light exposure without further molecular eye treatment has offered limited success including photocoagulation to halt pathological blood vessel growth or low light exposure to stimulate retinal cell viability. To add cellular specificity to such treatments, researchers have introduced various biological or chemical light‐sensing molecules and combined those with light exposure. (Pre‐)clinical trials describe the use of optogenetics and channelrhodpsins, i. e. light‐sensitive ion channels, in patient vision restoration. In the chemical arena, pharmacological agents, rendered light‐sensitive by reversible modification with photosensitive protecting compounds (“caging”), have been applied to eyes of living mice to photo‐release specific cellular activities. Among these were successful proof‐of‐principle experiments that were conducted to establish photo‐sensitive gene therapies in the eye. For light‐mediated treatment in combination with chemical biology, we wish to describe here the current frontiers of research in vision restoration with an eye on differences between biological and chemical light‐sensing molecules, patient requirements, and future outlooks.

Huang Y., Wu Z., Wang H., An H., Zhang J., Bao Z.

In this review, the design idea, synergistic mechanism and application prospects of l-arginine-loaded nanogenerators with cascade and synergistic NO/PDT for anti-tumor applications are summarized.

Knapp F., Hogenkamp F., Paik S., Jaeger K., Pietruszka J., Drepper T.

Photocaged compounds are chemical conjugates that are designed to release an active molecule upon exposure to light of a specific wavelength. In recent years, photocaged inducer molecules such as caged isopropyl β-d-1-thiogalactopyranoside (cIPTG) have been increasingly used as a powerful tool for light-driven gene expression in bacteria, allowing researchers to precisely and noninvasively tune the expression of specific target genes. In this chapter, we present a guideline for the synthesis of 6-nitropiperonyl photocaged IPTG (NP-cIPTG) as well as its in vivo application as an optochemical on-switch of gene transcription in Escherichia coli and other bacteria.

Virts N.A., Karogodina T.Y., Panfilov M.A., Vorob'ev A.Y., Moskalensky A.E.

ABSTRACTLocal therapeutic action and targeted drug release are promising approaches compared to traditional systemic drug administration. This is especially relevant for nitric oxide (NO), as its effects change dramatically depending on concentration and cellular context. Materials capable of releasing NO in deep tissues in a controlled manner might open new therapeutic opportunities. Light‐sensitive NO donors represent a fascinating class of compounds with significant potential for precise and controlled NO release. However, most of them are sensitive to visible light, with only a few examples absorbing in a near‐infrared therapeutic window. Here, we present the proof‐of‐concept of soft implants consisting of the photon upconverting core and the outer shell loaded with visible‐light triggered NO donor. The separation into two compartments results in efficient energy harvesting by the dye and effective NO release under 980 nm infrared irradiation. Such implants could be used in smart therapies implying well‐controlled and localized NO release.

Yu H., Ben-Akiva E., Meyer R.A., Green J.J.

Nidheesh P.V., Boczkaj G., Ganiyu S.O., Oladipo A.A., Fedorov K., Xiao R., Dionysiou D.D.

Contamination of drinking water sources with recalcitrant organic pollutants is a major health issue requiring advanced oxidation processes for the degradation of such pollutants. Here we review the use of advanced oxidation processes-based treatment of water, wastewater, and sludge, with focus on singlet oxygen production, reactivity mechanisms, and applications. Processes for single-oxygen production include photochemical production, decomposition of hydrogen peroxide, ozonides, endoperoxides, and sulfate radical-based advanced oxidation. Singlet oxygen is one of the main non-radical reactive oxygen species that are generated during advanced oxidation processes. It is less reactive but highly selective toward electron-rich organic compounds, compared to hydroxyl and sulfate radicals. When generated in large quantities, singlet oxygen can be the dominant reactive oxygen species responsible for the degradation of targeted pollutants. Singlet oxygen is less affected by water matrix components including dissolved organic matter and scavenging by anions.

Huber M., Schöbinger M., Cirera J., Stöger B., Weinberger P.

AbstractFour novel fluorescence active ligands (1–4) consisting of a 1H‐tetrazol‐1‐yl moiety as coordinating unit and a 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) derivative as fluorophore, bridged via alkyl (‐(CH2)n‐, n=1–3) or benzyl (‐CH2‐C6H4‐) spacers were designed. Successful synthesis is demonstrated by multinuclear NMR spectroscopy, as well as powder and single crystal XRD analysis. The methylene bridged ligand 2 (4,4‐difluoro‐1,3,5,7‐tetramethyl‐8‐[(1H‐tetrazol‐1‐yl)methyl]‐4‐bora‐3a,4a‐diaza‐s‐indacene) crystallizes in different polymorphs and solvatomorphs, in contrast to the other three ligands, which show no polymorphism under identical conditions. Photophysical studies revealed high fluorescence quantum yields (69 – 95 %) in solution for the ‐(CH2)2‐ bridged ligand 3 (4,4‐difluoro‐1,3,5,7‐tetramethyl‐8‐[(1H‐tetrazol‐1‐yl)ethyl]‐4‐bora‐3a,4a‐diaza‐s‐indacene) and the ‐(CH2)3‐ bridged ligand 4 (4,4‐difluoro‐1,3,5,7‐tetramethyl‐8‐[(1H‐tetrazol‐1‐yl)propyl]‐4‐bora‐3a,4a‐diaza‐s‐indacene). Non‐radiative decay due to rotational motion of the 1H‐tetrazol‐1‐yl‐ and/or ‐CH2‐C6H4‐ moiety for 2 and 1 (4,4‐difluoro‐1,3,5,7‐tetramethyl‐8‐[4‐((1H‐tetrazol‐1‐yl)methyl)phenyl]‐4‐bora‐3a,4a‐diaza‐s‐indacene) respectively leads to reduced quantum yields of ≥35 %. Complete fluorescence quenching upon aggregation is prevented by installation of the sterically demanding 1H‐tetrazol‐1‐yl moiety and a spacer in meso‐position of the BODIPY core to elongate the intermolecular distances between two adjacent BODIPY cores. Detailed photophysical and crystallographic investigations are supported by theoretical calculations.

Verveld W., de Wolf J.R., Legtenberg C.G., Knop T., Bosschaart N.

Starodubtseva E.S., Karogodina T.Y., Panfilov M.A., Sheven D.G., Selyutina O.Y., Vorob’ev A.Y., Moskalensky A.E.

Control of biological activity with light is a fascinating idea. “Caged” compounds, molecules modified with photolabile protecting group, are one of the instruments for this purpose. Adrenergic receptors are essential regulators of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. These receptors are largely used as pharmacologic targets. Photolabile “caged” analogs of adrenergic receptor agonists has been reported more than 30 years ago. We report that the photolysis of epinephrine analogs, apart from liberation of the epinephrine, is accompanied by a formation of significant amount of adrenochrome, a compound with neuro- and cardiotoxic effect.

Bobrov A., Usoltsev S., Moleva N., Marfin Y.

Starodubtseva E.S., Karogodina T.Y., Panfilov M.A., Sheven D.G., Selyutina O.Y., Vorob’ev A.Y., Moskalensky A.E.

Control of biological activity with light is a fascinating idea. “Caged” compounds, molecules modified with photolabile protecting group, are one of the instruments for this purpose. Adrenergic receptors are essential regulators of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. These receptors are largely used as pharmacologic targets. Photolabile “caged” analogs of adrenergic receptor agonists has been reported more than 30 years ago. We report that the photolysis of epinephrine analogs, apart from liberation of the epinephrine, is accompanied by a formation of significant amount of adrenochrome, a compound with neuro- and cardiotoxic effect.

Starodubtseva E.S., Karogodina T.Y., Moskalensky A.E.

Disorders of hemostasis resulting in bleeding or thrombosis are leading cause of mortality in the world. Blood platelets are main players in hemostasis, providing the primary response to the vessel wall injury. In this case, they rapidly switch to the activated state in reaction to the exposed chemical substances such as ADP, collagen and thrombin. Molecular mechanisms of platelet activation are known, and detailed computational models are available. However, they are too complicated for large-scale problems (e.g. simulation of the thrombus growth) where less detailed models are required, which still should take into account the variation of agonist concentration and heterogeneity of platelets. In this paper, we present a simple model of the platelet population response to a spatially inhomogeneous stimulus. First, computational nodes modeling platelets are placed randomly in space. Each platelet is assigned the specific threshold for agonist, which determines whether it becomes activated at a given time. The distribution of the threshold value in a population is assumed to be log-normal. The model was validated against experimental data in a specially designed system, where the photorelease of ADP was caused by localized laser stimulus. In this system, a concentration of ADP obeys 2-dimensional Gaussian distribution which broadens due to the diffusion. The response of platelets to the point-like source of ADP is successfully described by the presented model. Our results advance the understanding of platelet function during hemostatic response. The simulation approach can be incorporated into larger computational models of thrombus formation.

Virts N.A., Karogodina T.Y., Panfilov M.A., Vorob’ev A.Y., Moskalensky A.E.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Light-controllable NO releasers show promise in the development of smart therapies. Here, we present a novel biocompatible material based on polydimethylsiloxane (PDMS) doped with BODIPY derivatives containing an N-nitroso moiety that is capable of the photoinduced generation of NO. We study the green-light-induced NO-release properties with the following three methods: electrochemical gas-phase sensor, liquid-phase sensor, and the Griess assay. Prolonged release of NO from the polymer films after short irradiation by narrow-band LED light sources and a laser beam is demonstrated. Importantly, this was accompanied by no or little release of the parent compound (BODIPY-based photodonor). Silicone films with the capability of controllable and clean NO release can potentially be used as a highly portable NO delivery system for different therapeutic applications.

Liu L., Lv K., Wu X., Dong G., Ge Y., Shao Y., Li G., Ma D., Liu T.

Sink A., Gerwe H., Hübner H., Boivin‐Jahns V., Fender J., Lorenz K., Gmeiner P., Decker M.

Abstractβ2‐adrenergic receptor (β2‐AR) agonists are used for the treatment of asthma and chronic obstructive pulmonary disease, but also play a role in other complex disorders including cancer, diabetes and heart diseases. As the cellular and molecular mechanisms in various cells and tissues of the β2‐AR remain vastly elusive, we developed tools for this investigation with high temporal and spatial resolution. Several photoswitchable β2‐AR agonists with nanomolar activity were synthesized. The most potent agonist for β2‐AR with reasonable switching is a one‐digit nanomolar active, trans‐on arylazopyrazole‐based adrenaline derivative and comprises valuable photopharmacological properties for further biological studies with high structural accordance to the native ligand adrenaline.

Eluu S.C., Obayemi J.D., Salifu A.A., Yiporo D., Oko A.O., Aina T., Oparah J.C., Ezeala C.C., Etinosa P.O., Ugwu C.M., Esimone C.O., Soboyejo W.O.

AbstractTriple-negative breast cancer (TNBC) treatment is challenging and frequently characterized by an aggressive phenotype and low prognosis in comparison to other subtypes. This paper presents fabricated implantable drug-loaded microporous poly-di-methyl-siloxane (PDMS) devices for the delivery of targeted therapeutic agents [Luteinizing Hormone-Releasing Hormone conjugated paclitaxel (PTX-LHRH) and Luteinizing Hormone-Releasing Hormone conjugated prodigiosin (PG-LHRH)] for the treatment and possible prevention of triple-negative cancer recurrence. In vitro assessment using the Alamar blue assay demonstrated a significant reduction (p < 0.05) in percentage of cell growth in a time-dependent manner in the groups treated with PG, PG-LHRH, PTX, and PTX-LHRH. Subcutaneous triple-negative xenograft breast tumors were then induced in athymic female nude mice that were four weeks old. Two weeks later, the tumors were surgically but partially removed, and the device implanted. Mice were observed for tumor regrowth and organ toxicity. The animal study revealed that there was no tumor regrowth, six weeks post-treatment, when the LHRH targeted drugs (LHRH-PTX and LHRH-PGS) were used for the treatment. The possible cytotoxic effects of the released drugs on the liver, kidney, and lung are assessed using quantitative biochemical assay from blood samples of the treatment groups. Ex vivo histopathological results from organ tissues showed that the targeted cancer drugs released from the implantable drug-loaded device did not induce any adverse effect on the liver, kidneys, or lungs, based on the results of qualitative toxicity studies. The implications of the results are discussed for the targeted and localized treatment of triple negative breast cancer.

Long K., Lv W., Wang Z., Zhang Y., Chen K., Fan N., Li F., Zhang Y., Wang W.

AbstractProdrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm2, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.

Panfilov M.A., Karogodina T.Y., Sibiryakova A.A., Tretyakova I.S., Vorob'ev A.Y., Moskalensky A.E.

AbstractNitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short lifetime in physiological conditions and local action impede direct application in medicine because highly targeted NO‐delivery systems are required. Light‐controllable NO releasers are promising for the development of smart therapies. Here we present simply prepared meso‐aminomethyl BODIPY (4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene) derivatives containing N‐nitroso moiety, which show the photoinduced generation of NO in a solution. These compounds can additionally generate singlet oxygen, and NO/1O2 generation efficiency can be tuned by substituents. As an example of NO‐mediated effect, we demonstrate light‐dependent inhibition of platelet activation in vitro. The presented compounds could serve as the basis for the development of novel hybrid therapeutic methods.

Chai Y., Shangguan L., Yu H., Sun Y., Huang X., Zhu Y., Wang H., Liu Y.

AbstractAtherosclerosis is a chronic inflammatory disease that affects arteries and is the main cause of cardiovascular disease. Atherosclerotic plaque formation is usually asymptomatic and does not manifest until the occurrence of clinical events. Therefore, early diagnosis and treatment of atherosclerotic plaques is particularly important. Here, a series of NIR‐II fluorescent dyes (RBT‐NH) are developed for three photoresponsive NO prodrugs (RBT‐NO), which can be controllably triggered by 808 nm laser to release NO and turn on the NIR‐II emission in the clinical medicine “therapeutic window”. Notably, RBT3‐NO is selected for its exhibited high NO releasing efficiency and superior fluorescence signal enhancement. Subsequently, a platelet‐mimicking nano‐prodrug system (RBT3‐NO‐PEG@PM) is constructed by DSPE‐mPEG5k and platelet membrane (PM) for effectively targeted diagnosis and therapy of atherosclerosis in mice. The results indicate that this platelet‐mimicking NO nano‐prodrug system can reduce the accumulation of lipids at the sites of atherosclerotic plaques, improve the inflammatory response at the lesion sites, and promote endothelial cell migration, thereby slowing the progression of plaques.

Shankar K.N., Diamond S.L., Sinno T.

Thrombus growth is a complex and multiscale process involving interactions spanning length scales from individual micron-sized platelets to macroscopic clots at the millimeter scale. Here, we describe a 3D multiscale framework to simulate thrombus growth under flow comprising four individually parallelized and coupled modules: a data-driven Neural Network (NN) that accounts for platelet calcium signaling, a Lattice Kinetic Monte Carlo (LKMC) simulation for tracking platelet positions, a Finite Volume Method (FVM) simulator for solving convection-diffusion-reaction equations describing agonist release and transport, and a Lattice Boltzmann (LB) flow solver for computing the blood flow field over the growing thrombus. Parallelization was achieved by developing in-house parallel routines for NN and LKMC, while the open-source libraries OpenFOAM and Palabos were used for FVM and LB, respectively. Importantly, the parallel LKMC solver utilizes particle-based parallel decomposition allowing efficient use of cores over highly heterogeneous regions of the domain. The parallelized model was validated against a reference serial version for accuracy, demonstrating comparable results for both microfluidic and stenotic arterial clotting conditions. Moreover, the parallelized framework was shown to scale essentially linearly on up to 64 cores. Overall, the parallelized multiscale framework described here is demonstrated to be a promising approach for studying single-platelet resolved thrombosis at length scales that are sufficiently large to directly simulate coronary blood vessels.

Andrabi S.M., Sharma N.S., Karan A., Shahriar S.M., Cordon B., Ma B., Xie J.

AbstractNitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half‐life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO‐releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO‐releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems.

Volkov V., Lobanov A., Voronkov M., Baygildiev T., Misin V., Tsivileva O.

Superoxide is the primary active oxygen form produced in living organisms. Because of superoxide anion radical formation during epinephrine oxidation in alkaline medium, this system is offered in some works for antioxidant activity analysis, however, without enough physicochemical justification. Therefore, the task of developing reliable methods for analyzing the superoxide inhibition activity of various objects is very urgent. In this work, a kinetic model of epinephrine autoxidation in an alkaline medium in the presence of antioxidants of plant origin is proposed. The participation of chain reactions with long oxidation chains in this process is revealed. The limiting stage of the process is a one-electron reduction of oxygen by the anionic forms of the phenolic hydroxyls of epinephrine. The appearance of the absorption maximum at a wavelength of 347 nm during epinephrine autoxidation is associated with adrenolutin formation, which is confirmed by HPLC/UV/MS. No adduct formation between phenolic antioxidants and epinephrine oxidation products was found. The complex U-shaped character of epinephrine autoxidation rate dependence on the content of antioxidants in the reaction system was shown. The study of the kinetics of epinephrine autoxidation in the presence of an individual phenolic plant superoxide inhibitor, chlorogenic acid, was carried out for the first time. The inhibitory effect of yarrow, chamomile, and bur beggar-ticks plant extracts in the adrenaline system was examined.

Ezike T.C., Okpala U.S., Onoja U.L., Nwike C.P., Ezeako E.C., Okpara O.J., Okoroafor C.C., Eze S.C., Kalu O.L., Odoh E.C., Nwadike U.G., Ogbodo J.O., Umeh B.U., Ossai E.C., Nwanguma B.C.

Advances in molecular pharmacology and an improved understanding of the mechanism of most diseases have created the need to specifically target the cells involved in the initiation and progression of diseases. This is especially true for most life-threatening diseases requiring therapeutic agents which have numerous side effects, thus requiring accurate tissue targeting to minimize systemic exposure. Recent drug delivery systems (DDS) are formulated using advanced technology to accelerate systemic drug delivery to the specific target site, maximizing therapeutic efficacy and minimizing off-target accumulation in the body. As a result, they play an important role in disease management and treatment. Recent DDS offer greater advantages when compared to conventional drug delivery systems due to their enhanced performance, automation, precision, and efficacy. They are made of nanomaterials or miniaturized devices with multifunctional components that are biocompatible, biodegradable, and have high viscoelasticity with an extended circulating half-life. This review, therefore, provides a comprehensive insight into the history and technological advancement of drug delivery systems. It updates the most recent drug delivery systems, their therapeutic applications, challenges associated with their use, and future directions for improved performance and use.

Panfilov M., Karogodina T., Sibiryakova A., Tretyakova I., Vorob’ev A., Moskalensky A.

Nitric oxide (NO) is a unique biochemical mediator involved in the regulation of vital processes. Its short lifetime in physiological conditions and local action impede direct application in medicine because highly targeted NO-delivery systems are required. Light-controllable NO releasers are promising for the development of smart therapies. Here we present simply prepared meso-aminomethyl BODIPY derivatives containing N-nitroso moiety, which show the photoinduced generation of NO in a solution. These compounds can additionally generate singlet oxygen, and NO/1O2 generation efficiency can be tuned by substituents. As an example of NO-mediated effect, we demonstrate light-dependent inhibition of platelet activation in vitro. The presented compounds could serve as the basis for the development of novel hybrid therapeutic methods.

Sarabando S.N., Palmeira A., Sousa M.E., Faustino M.A., Monteiro C.J.

Photopharmacology is an approach that aims to be an alternative to classical chemotherapy. Herein, the different classes of photoswitches and photocleavage compounds and their biological applications are described. Proteolysis targeting chimeras (PROTACs) containing azobenzene moieties (PHOTACs) and photocleavable protecting groups (photocaged PROTACs) are also mentioned. Furthermore, porphyrins are referenced as successful photoactive compounds in a clinical context, such as in the photodynamic therapy of tumours as well as preventing antimicrobial resistance, namely in bacteria. Porphyrins combining photoswitches and photocleavage systems are highlighted, taking advantage of both photopharmacology and photodynamic action. Finally, porphyrins with antibacterial activity are described, taking advantage of the synergistic effect of photodynamic treatment and antibiotic therapy to overcome bacterial resistance.