Publications by authors named "Nina N Peskova"

7 Publications

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The localization of the photosensitizer determines the dynamics of the secondary production of hydrogen peroxide in cell cytoplasm and mitochondria.

J Photochem Photobiol B 2021 Jun 6;219:112208. Epub 2021 May 6.

Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia. Electronic address:

Photodynamic therapy (PDT) is based on the production of the cytotoxic reactive oxygen species (ROS) by light irradiation of a photosensitizer dye in the presence of molecular oxygen. Along with photochemical ROS production, it becomes evident that PDT induces massive secondary production of ROS which is registered long after the irradiation is completed. We created cell lines of human epidermoid carcinoma with the cytoplasmic and mitochondrial localization of protein sensor HyPer sensitive to hydrogen peroxide to compare its concentration in two cellular compartments. The lag-period between irradiation and accumulation of hydrogen peroxide in cells was registered; its duration was dose-dependent and increased up to 80 min when lowering the exposition dose from 50 to 15 J/cm. We have shown that localization of the photosensitizer determines the spatiotemporal pattern of the cell response to PDT: secondary hydrogen peroxide accumulation in cell cytoplasm induced by photodynamic treatment with lysosome-localized phtalocyianine Photosens occurs several minutes prior to that in mitochondria; on the contrary, membranotropic arylcyanoporphyrazine dye leads to massive mitochondrial hydrogen peroxide production followed by its cytoplasmic accumulation. We hypothesize that photosensitizers with various physicochemical properties and intracellular localization can trigger different patterns not only of primary but also secondary ROS production leading to different cell fate outcomes.
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http://dx.doi.org/10.1016/j.jphotobiol.2021.112208DOI Listing
June 2021

Novel porphyrazine-based photodynamic anti-cancer therapy induces immunogenic cell death.

Sci Rep 2021 Mar 30;11(1):7205. Epub 2021 Mar 30.

Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russian Federation.

The immunogenicity of dying cancer cells determines the efficacy of anti-cancer therapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD), which is characterized by the emission of damage-associated molecular patterns (DAMPs) from dying cells. This emission can trigger effective anti-tumor immunity. Only a few photosensitizers are known to induce ICD and, therefore, there is a need for development of new photosensitizers that can induce ICD. The purpose of this work was to analyze whether photosensitizers developed in-house from porphyrazines (pz I and pz III) can induce ICD in vitro and in vivo when used in PDT. We indetified the optimal concentrations of the photosensitizers and found that, at a light dose of 20 J/cm (λ 615-635 nm), both pz I and pz III efficiently induced cell death in cancer cells. We demonstrate that pz I localized predominantly in the Golgi apparatus and lysosomes while pz III in the endoplasmic reticulum and lysosomes. The cell death induced by pz I-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) but not by ferrostatin-1 and DFO (ferroptosis inhibitors) or by necrostatin-1 s (necroptosis inhibitor). By contrast, the cell death induced by pz III-PDT was inhibited by z-VAD-fmk and by the necroptosis inhibitor, necrostatin-1 s. Cancer cells induced by pz I-PDT or pz III-PDT released HMGB1 and ATP and were engulfed by bone marrow-derived dendritic cells, which then matured and became activated in vitro. We demonstrate that cancer cells, after induction of cell death by pz I-PDT or pz III-PDT, are protective when used in the mouse model of prophylactic tumor vaccination. By vaccinating immunodeficient mice, we prove the role of the adaptive immune system in protecting against tumours. All together, we have shown that two novel porphyrazines developed in-house are potent ICD inducers that could be effectively applied in PDT of cancer.
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http://dx.doi.org/10.1038/s41598-021-86354-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010109PMC
March 2021

Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine.

J Immunother Cancer 2019 12 16;7(1):350. Epub 2019 Dec 16.

Cell Death Investigation and Therapy Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.

Background: Anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT).

Methods: Cell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11cCD86, CD11cCD40) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model.

Results: We determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm (λex 615-635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo.

Conclusions: Altogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy.
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http://dx.doi.org/10.1186/s40425-019-0826-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916435PMC
December 2019

Effect of novel porphyrazine photosensitizers on normal and tumor brain cells.

J Biophotonics 2020 01 17;13(1):e201960077. Epub 2019 Oct 17.

Institute of Biology and Biomedicine, Lobachevsky State University of Nizhni Novgorod, Nizhny Novgorod, Russian Federation.

Photodynamic therapy (PDT) is a clinically approved procedure for targeting tumor cells. Though several different photosensitizers have been developed, there is still much demand for novel photosensitizers with improved properties. In this study we aim to characterize the accumulation, localization and dark cytotoxicity of the novel photosensitizers developed in-house derivatives of porphyrazines (pz I-IV) in primary murine neuronal cells, as well as to identify the concentrations at which pz still effectively induces death in glioma cells yet is nontoxic to nontransformed cells. The study shows that incubation of primary neuronal and glioma cells with pz I-IV leads to their accumulation in both types of cells, but their rates of internalization, subcellular localization and dark toxicity differ significantly. Pz II was the most promising photosensitizer. It efficiently killed glioma cells while remaining nontoxic to primary neuronal cells. This opens up the possibility of evaluating pz II for experimental PDT for glioma.
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http://dx.doi.org/10.1002/jbio.201960077DOI Listing
January 2020

Synthesis and biological evaluation of new water-soluble photoactive chlorin conjugate for targeted delivery.

Eur J Med Chem 2018 Jan 19;144:740-750. Epub 2017 Dec 19.

Lobachevsky State University of Nizhny Novgorod, Gagarina Av. 23, Nizhny Novgorod 603950, Russian Federation. Electronic address:

A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC/IC ratio of 11-18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.
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http://dx.doi.org/10.1016/j.ejmech.2017.12.062DOI Listing
January 2018

Monitoring of hydrogen peroxide production under photodynamic treatment using protein sensor HyPer.

J Photochem Photobiol B 2018 Jan 17;178:296-301. Epub 2017 Nov 17.

Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia. Electronic address:

An interest to HO accumulation under photodynamic treatment can be explained by its participation in intracellular signal cascades. It is important not only to detect HO generation, but also to trace the dynamics of its intracellular content. In the present study the dynamics of cellular HO content under photodynamic treatment was analyzed using genetically encoded reversible HO-sensitive sensor HyPer. Real-time detecting of HO production after photodynamic treatment was performed using the protein sensor and individual features of action of different photosensitizers were revealed. Photodynamic treatment with a number of chlorin and phthalocyanine photosensitizers was found to induce secondary production of HO in the cells. Three types of dynamic responses were registered: monotonous increase of HO level during the entire observation time in the presence of Fotoditazin and Holosens; transient short-term accumulation in the presence of Radachlorin and Phthalosens; and relatively low-level stable increase in the presence of Photosens. The listed photosensitizers differ significantly in intracellular localization and physicochemical properties, which can determine the differences in the response of HO after the photodynamic treatment. In general, it has been shown that the rapid transient HO response is typical for hydrophobic compounds localized in membrane cell structures, whereas in the presence of more hydrophilic dyes a prolonged monotonous HO accumulation occurs.
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http://dx.doi.org/10.1016/j.jphotobiol.2017.11.020DOI Listing
January 2018

Effective delivery of porphyrazine photosensitizers to cancer cells by polymer brush nanocontainers.

J Biophotonics 2017 Sep 28;10(9):1189-1197. Epub 2016 Nov 28.

Lobachevsky University, Gagarina ave. 23, 603950, Nizhny Novgorod, Russia.

Efficient drug delivery can be assigned to tasks that attract the most acute attention of researchers in the field of anticancer drug design. We have reported the first case of using amphiphilic polymer brushes as nanocontainers for photosensitizer delivery to cancer cells. Regular graft-copolymers of hydrophobic polyimides with hydrophilic polymethacrylic acid side chains were loaded with photosensitive dye tetra(4-fluorophenyl)tetracyanoporphyrazine (Pz) providing a sufficiently stable homogeneous fraction of fluorescent Pz-loaded nanoparticles with a size of 100-150 nm. Pz-loaded polymer brushes were substantially more efficient for Pz delivery into cells compared with other types of particles examined, Pz-polyethyleneglycol and Pz-methylcellulose. In vivo, an efficient Pz delivery to tumor can also be expected since the Pz-PB particle size is in the optimal range for passive targeting. Pz-PB showed pronounced photodynamic activity, while, that is important, in the absence of irradiation the PB carrier itself was significantly less toxic than the dye itself. Summing up, water-soluble polymer brushes with polyimide backbones and polymethacrylic acid side chains can be regarded as a novel type of nanocontainers providing efficient intracellular drug delivery for photodynamic therapy of cancers.
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http://dx.doi.org/10.1002/jbio.201600212DOI Listing
September 2017