Publications by authors named "Larisa G Klapshina"

10 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

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

Liposomal Form of Tetra(Aryl)Tetracyanoporphyrazine: Physical Properties and Photodynamic Activity In Vitro.

J Fluoresc 2018 Mar 26;28(2):513-522. Epub 2018 Jan 26.

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

Tetra(aryl)tetracyanoporphyrazines are the promising group of dyes for photodynamic therapy of tumors with unique combination of photosensitizer properties and sensitivity of fluorescence parameters to the environment viscosity. However, in vivo application of such hydrophobic photosensitizers requires using of drug carriers ensuring efficient delivery to the tumor site. The present study is focused on obtaining liposomes loaded with tetrakis(4-benzyloxyphenyl)tetracyanoporphyrazine and examining their properties depending on lipid composition. An efficient loading of the dye and a high long-term stability were proved for the liposomes composed of phosphatidylcholine with cholesterol and phosphatidylglycerol. This can be explained by the presence of negatively charged lipids in the bilayer and, as a consequence, a high value of the surface potential. A high rate of cellular uptake and a strong photoinduced toxicity give the prerequisites for the further use of the liposomal form of the photosensitizer for photodynamic therapy of tumors.
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http://dx.doi.org/10.1007/s10895-018-2212-9DOI Listing
March 2018

In vivo multimodal tumor imaging and photodynamic therapy with novel theranostic agents based on the porphyrazine framework-chelated gadolinium (III) cation.

Biochim Biophys Acta Gen Subj 2017 Dec 13;1861(12):3120-3130. Epub 2017 Sep 13.

Nizhny Novgorod State Medical Academy, 10/1 Minin and Pozharsky Sq., 603005 Nizhny Novgorod, Russia.

Background: A promising strategy for cancer diagnosis and therapy is the development of an agent for multimodal imaging and treatment. In the present paper we report on two novel multifunctional agents prepared on the porphyrazine pigment platform using a gadolinium (III) cation chelated by red-fluorescent tetrapyrrole macrocycles (GdPz1 and GdPz2).

Methods: Spectral and magnetic properties of the compounds were analyzed. Monitoring of GdPz1 and GdPz2 accumulation in the murine colon carcinoma CT26 was performed in vivo using fluorescence imaging and MRI. The photobleaching of GdPz1 or GdPz2 and tumor growth rate after photodynamic therapy (PDT) were assessed.

Results: GdPz1 and GdPz2 demonstrated the selective accumulation in tumor that was indicated by higher fluorescence intensity in the tumor area in comparison with the normal tissues. The results of MRI in vivo showed that GdPz1 or GdPz2 provided significant contrast enhancement of the tumor in T1 MR images. PDT with GdPz2 resulted in ~20% decrease in fluorescence intensity of the compound and the inhibition of tumor growth.

Conclusions: We assessed the efficiency of two innovative Gd(III) cation-porphyrazine chelates as bimodal MR and fluorescent probes and photosensitizers for PDT and showed their potentials for tumor diagnostics and treatment.

General Significance: Water-soluble structures simple in preparation and administration into the body represent special interest for theranostics of tumors. Novel porphyrazine macrocycles chelating a central gadolinium cation demonstrated a good prospect as effective multimodal agents, representing a new approach to MRI and fluorescence imaging guided PDT.
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http://dx.doi.org/10.1016/j.bbagen.2017.09.004DOI Listing
December 2017

Imaging tumor microscopic viscosity in vivo using molecular rotors.

Sci Rep 2017 01 30;7:41097. Epub 2017 Jan 30.

Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK.

The microscopic viscosity plays an essential role in cellular biophysics by controlling the rates of diffusion and bimolecular reactions within the cell interior. While several approaches have emerged that have allowed the measurement of viscosity and diffusion on a single cell level in vitro, the in vivo viscosity monitoring has not yet been realized. Here we report the use of fluorescent molecular rotors in combination with Fluorescence Lifetime Imaging Microscopy (FLIM) to image microscopic viscosity in vivo, both on a single cell level and in connecting tissues of subcutaneous tumors in mice. We find that viscosities recorded from single tumor cells in vivo correlate well with the in vitro values from the same cancer cell line. Importantly, our new method allows both imaging and dynamic monitoring of viscosity changes in real time in live animals and thus it is particularly suitable for diagnostics and monitoring of the progress of treatments that might be accompanied by changes in microscopic viscosity.
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http://dx.doi.org/10.1038/srep41097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278387PMC
January 2017

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

Dual use of porphyrazines as sensitizers and viscosity markers in photodynamic therapy.

J Mater Chem B 2015 Feb 18;3(6):1089-1096. Epub 2014 Dec 18.

Department of Chemistry, Imperial College London, Exhibition Road, London SW7 2AZ, UK.

Porphyrazines have recently emerged as a useful class of tetrapyrroles suitable for photodynamic therapy of cancer (PDT) with excellent uptake and retention properties in vivo. Here we demonstrate that the photophysical properties of cyano-aryl porphyrazine pz1 are strongly viscosity dependent, i.e. the fluorescence lifetime and the quantum yield of pz1 increase as a function of solution viscosity. We have calibrated pz1 as a red-emitting fluorescent 'molecular rotor' in a large range of viscosities from 80 to ca. 5500 cP, in solutions of various solvent compositions and temperatures. On the other hand, pz1 works as an efficient PDT sensitiser, i.e. it induces apoptosis and necrosis in cells upon irradiation with red light through formation of singlet oxygen. We demonstrate that PDT in cells using pz1 is accompanied by a significant viscosity increase by monitoring the fluorescence lifetime of the rotor. We suggest that this increase could be used as a completely new type of diagnostic and dosimetry tool in a PDT treatment.
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http://dx.doi.org/10.1039/c4tb01678eDOI Listing
February 2015

Novel PEG-organized biocompatible fluorescent nanoparticles doped with an ytterbium cyanoporphyrazine complex for biophotonic applications.

Chem Commun (Camb) 2010 Nov 7;46(44):8398-400. Epub 2010 Oct 7.

G. A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences, Tropinin Street 49, GSP-445, Nizhny Novgorod, 603600, Russia.

The preparation and properties are described of two types of novel PEG-organized nanoparticles including silica-modified uniform disk-shaped nanoparticles doped with a fluorescent ytterbium cyanoporphyrazine complex; a large enhancement of red emission for both types of nanoparticles is observed in physiological liquids owing to their binding to biomolecules.
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http://dx.doi.org/10.1039/c0cc02842hDOI Listing
November 2010

Metal template assembly of highly functionalized octacyanoporphyrazine framework from TCNE structural units.

Chem Commun (Camb) 2007 May(19):1942-4

G. A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences, Tropinin Street 49, GSP-445, Nizhny Novgorod, 603600, Russia.

A new route to the octacyanoporphyrazine framework based on the interaction of metal sandwich pi-complexes with TCNE has been developed.
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http://dx.doi.org/10.1039/b701994gDOI Listing
May 2007