Publications by authors named "Irina V Balalaeva"

27 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphotobiol.2021.112208DOI Listing
June 2021

Controlled Formation of a Protein Corona Composed of Denatured BSA on Upconversion Nanoparticles Improves Their Colloidal Stability.

Materials (Basel) 2021 Mar 28;14(7). Epub 2021 Mar 28.

Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.

In the natural fluidic environment of a biological system, nanoparticles swiftly adsorb plasma proteins on their surface forming a "protein corona", which profoundly and often adversely affects their residence in the systemic circulation in vivo and their interaction with cells in vitro. It has been recognized that preformation of a protein corona under controlled conditions ameliorates the protein corona effects, including colloidal stability in serum solutions. We report on the investigation of the stabilizing effects of a denatured bovine serum albumin (dBSA) protein corona formed on the surface of upconversion nanoparticles (UCNPs). UCNPs were chosen as a nanoparticle model due to their unique photoluminescent properties suitable for background-free biological imaging and sensing. UCNP surface was modified with nitrosonium tetrafluoroborate (NOBF) to render it hydrophilic. UCNP-NOBF nanoparticles were incubated in dBSA solution to form a dBSA corona followed up by lyophilization. As produced dBSA-UCNP-NOBF demonstrated high photoluminescence brightness, sustained colloidal stability after long-term storage and the reduced level of serum protein surface adsorption. These results show promise of dBSA-based nanoparticle pretreatment to improve the amiability to biological environments towards theranostic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ma14071657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037850PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86354-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010109PMC
March 2021

Ferroptosis and Photodynamic Therapy Synergism: Enhancing Anticancer Treatment.

Trends Cancer 2021 Jun 25;7(6):484-487. Epub 2021 Feb 25.

Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russian Federation; Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent, Ghent, Belgium. Electronic address:

Photodynamic therapy (PDT) is widely used in cancer treatment; however, several challenges compromise its efficiency. We propose a synergistic action between PDT and ferroptotic cell death. PDT acts as a source of reactive oxygen species for the Fenton reaction, which may reinforce ferroptosis induction and increase PDT efficacy in anticancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2021.01.013DOI Listing
June 2021

Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future.

J Immunother Cancer 2021 Jan;9(1)

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

The past decade has witnessed major breakthroughs in cancer immunotherapy. This development has been largely motivated by cancer cell evasion of immunological control and consequent tumor resistance to conventional therapies. Immunogenic cell death (ICD) is considered one of the most promising ways to achieve total tumor cell elimination. It activates the T-cell adaptive immune response and results in the formation of long-term immunological memory. ICD can be triggered by many anticancer treatment modalities, including photodynamic therapy (PDT). In this review, we first discuss the role of PDT based on several classes of photosensitizers, including porphyrins and non-porphyrins, and critically evaluate their potential role in ICD induction. We emphasize the emerging trend of ICD induction by PDT in combination with nanotechnology, which represents third-generation photosensitizers and involves targeted induction of ICD by PDT. However, PDT also has some limitations, including the reduced efficiency of ICD induction in the hypoxic tumor microenvironment. Therefore, we critically evaluate strategies for overcoming this limitation, which is essential for increasing PDT efficiency. In the final part, we suggest several areas for future research for personalized cancer immunotherapy, including strategies based on oxygen-boosted PDT and nanoparticles. In conclusion, the insights from the last several years increasingly support the idea that PDT is a powerful strategy for inducing ICD in experimental cancer therapy. However, most studies have focused on mouse models, but it is necessary to validate this strategy in clinical settings, which will be a challenging research area in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802670PMC
January 2021

Comparative Analysis of Cell-Cell Contact Abundance in Ovarian Carcinoma Cells Cultured in Two- and Three-Dimensional In Vitro Models.

Biology (Basel) 2020 Dec 4;9(12). Epub 2020 Dec 4.

The Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, Russia.

Tumor resistance to therapy is associated with the 3D organization and peculiarities of the tumor microenvironment, of which intercellular adhesion is a key participant. In this work, the abundance of contact proteins was compared in SKOV-3 and SKOV-3.ip human ovarian adenocarcinoma cell lines, cultivated in monolayers, tumor spheroids and collagen hydrogels. Three-dimensional models were characterized by extremely low expression of basic molecules of adherens junctions E-cadherin and demonstrated a simultaneous decrease in desmosomal protein desmoglein-2, gap junction protein connexin-43 and tight junction proteins occludin and ZO-1. The reduction in the level of contact proteins was most pronounced in collagen hydrogel, accompanied by significantly increased resistance to treatment with doxorubicin and targeted anticancer toxin DARPin-LoPE. Thus, we suggest that 3D models of ovarian cancer, especially matrix-based models, tend to recapitulate tumor microenvironment and treatment responsiveness to a greater extent than monolayer culture, so they can be used as a highly relevant platform for drug efficiency evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology9120446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761996PMC
December 2020

UCNP-based Photoluminescent Nanomedicines for Targeted Imaging and Theranostics of Cancer.

Molecules 2020 Sep 19;25(18). Epub 2020 Sep 19.

Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.

Theranostic approach is currently among the fastest growing trends in cancer treatment. It implies the creation of multifunctional agents for simultaneous precise diagnosis and targeted impact on tumor cells. A new type of theranostic complexes was created based on NaYF: Yb,Tm upconversion nanoparticles coated with polyethylene glycol and functionalized with the HER2-specific recombinant targeted toxin DARPin-LoPE. The obtained agents bind to HER2-overexpressing human breast adenocarcinoma cells and demonstrate selective cytotoxicity against this type of cancer cells. Using fluorescent human breast adenocarcinoma xenograft models, the possibility of intravital visualization of the UCNP-based complexes biodistribution and accumulation in tumor was demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25184302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571190PMC
September 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-019-0826-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916435PMC
December 2019

Water-Soluble Chlorin/Arylaminoquinazoline Conjugate for Photodynamic and Targeted Therapy.

J Med Chem 2019 12 13;62(24):11182-11193. Epub 2019 Dec 13.

Lobachevsky State University of Nizhny Novgorod , Gagarina Avenue 23 , Nizhny Novgorod 603950 , Russia.

A new water-soluble conjugate, consisting of a chlorin- photosensitizer part, a 4-arylaminoquinazoline moiety with affinity to epidermal growth factor receptors, and a hydrophilic β-d-maltose fragment, was synthesized starting from methylpheophorbide- in seven steps. The prepared conjugate exhibited low levels of dark cytotoxicity and pronounced photoinduced cytotoxicity at submicromolar concentrations in vitro, with an IC(dark)/IC(light) ratio of ∼368 and a singlet oxygen quantum yield of about 20%. In tumor-bearing Balb/c nude mice, conjugate preferentially accumulates in the tumor tissue. Irradiation of the nude mice bearing A431 xenograft tumors after intravenous administration of the prepared conjugate with a relatively low light dose (50 J/cm) produced an excellent therapeutic effect with profound tumor regression and low systemic toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b01294DOI Listing
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbio.201960077DOI Listing
January 2020

HER2-Specific Targeted Toxin DARPin-LoPE: Immunogenicity and Antitumor Effect on Intraperitoneal Ovarian Cancer Xenograft Model.

Int J Mol Sci 2019 May 15;20(10). Epub 2019 May 15.

Laboratory of Molecular Immunology, Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklay St., Moscow 117997, Russia.

High immunogenicity and systemic toxicity are the main obstacles limiting the clinical use of the therapeutic agents based on exotoxin A. In this work, we studied the immunogenicity, general toxicity and antitumor effect of the targeted toxin DARPin-LoPE composed of HER2-specific DARPin and a low immunogenic exotoxin A fragment lacking immunodominant human B lymphocyte epitopes. The targeted toxin has been shown to effectively inhibit the growth of HER2-positive human ovarian carcinoma xenografts, while exhibiting low non-specific toxicity and side effects, such as vascular leak syndrome and liver tissue degradation, as well as low immunogenicity, as was shown by specific antibody titer. This represents prospects for its use as an agent for targeted therapy of HER2-positive tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20102399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567818PMC
May 2019

Preclinical Study of Biofunctional Polymer-Coated Upconversion Nanoparticles.

Toxicol Sci 2019 07;170(1):123-132

Nizhny Novgorod State University, Nizhny Novgorod 603022, Russia.

Upconversion nanoparticles (UCNPs) are new-generation photoluminescent nanomaterials gaining considerable recognition in the life sciences due to their unique optical properties that allow high-contrast imaging in cells and tissues. Upconversion nanoparticle applications in optical diagnosis, bioassays, therapeutics, photodynamic therapy, drug delivery, and light-controlled release of drugs are promising, demanding a comprehensive systematic study of their pharmacological properties. We report on production of biofunctional UCNP-based nanocomplexes suitable for optical microscopy and imaging of HER2-positive cells and tumors, as well as on the comprehensive evaluation of their pharmacokinetics, pharmacodynamics, and toxicological properties using cells and laboratory animals. The nanocomplexes represent a UCNP core/shell structure of the NaYF4:Yb, Er, Tm/NaYF4 composition coated with an amphiphilic alternating copolymer of maleic anhydride with 1-octadecene (PMAO) and conjugated to the Designed Ankyrin Repeat Protein (DARPin 9_29) with high affinity to the HER2 receptor. We demonstrated the specific binding of UCNP-PMAO-DARPin to HER2-positive cancer cells in cultures and xenograft animal models allowing the tumor visualization for at least 24 h. An exhaustive study of the general and specific toxicity of UCNP-PMAO-DARPin including the evaluation of their allergenic, immunotoxic, and reprotoxic properties was carried out. The obtained experimental body of evidence leads to a conclusion that UCNP-PMAO and UCNP-PMAO-DARPin are functional, noncytotoxic, biocompatible, and safe for imaging applications in cells, small animals, and prospective clinical applications of image-guided surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfz086DOI Listing
July 2019

Low-level laser therapy as a modifier of erythrocytes morphokinetic parameters in hyperadrenalinemia.

Lasers Med Sci 2019 Oct 4;34(8):1603-1612. Epub 2019 Mar 4.

Department of Physiology and Biochemistry of Animals, Nizhny Novgorod State Agricultural Academy, 97 Gagarin Ave., Nizhny Novgorod, 603107, Russia.

Low-level laser therapy (LLLT) is widely used in clinical practice for treatment of various pathologies. It is assumed that LLLT impact on microcirculation is among the mechanisms underlying its therapeutic effect. The microcirculation disorder is observed in the pathogenesis of any inflammatory process and is significantly influenced by red blood cells (RBCs). On this point, studying the RBCs morphology under the influence of LLLT on alterated organism is of scientific interest and practical importance. The aim of the present study was to analyze the LLLT effect on morphokinetic parameters of RBCs in hyperadrenalinemia. The LLLT effect was analyzed on rats intraperitoneally injected with adrenaline hydrochloride solution (0.1 mg/kg). As the comparison groups, the effects of LLLT, adrenaline, or saline injection as well as the parameters of intact animals were studied. LLLT was applied on the occipital region of rats for 10 min. The light irradiation with pulse frequency 415 Hz at 890 nm wavelength and average power density in the plane of the output window at 193 μW/cm was used. The dynamics of morphological characteristics of RBCs was studied by phase interference microscopy; the RBC electrophoretic mobility was tested by microelectrophoresis technique; photometric analyses of the RBCs amount, hemoglobin content, and osmotic fragility were performed. The adrenaline injection resulted in a significant increase in the amount of RBC pathological forms and a decrease in discocytes and normocytes by more than 50%. An increase in the optical density of RBC phase portraits, a decline in osmotic resistance, and electronegativity of RBC membranes and a reduction of their number in peripheral blood were also registered. The revealed effects persisted for 1 week after the adrenaline administration. LLLT did not significantly impact on the RBC parameters 1 h after adrenaline injection. However, a day later, LLLT reduced the severity of the adrenaline effect on RBSs, which was manifested in a decreased amount of the pathological forms of RBCs, restored RBC phase portraits, higher electrophoretic mobility and osmotic resistance, and RBSs amount in peripheral blood restored up to the level of intact animals. We suppose that the mechanism of LLLT action is realized both at cellular level through the laser radiation effect on RBC membranes, and at systemic level through the activation of stress-realizing systems of the organism with subsequent limitation of inflammatory response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10103-019-02755-yDOI Listing
October 2019

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency.

Cancers (Basel) 2019 Jan 10;11(1). Epub 2019 Jan 10.

The Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia.

Malignant tumors are characterized by structural and molecular peculiarities providing a possibility to directionally deliver antitumor drugs with minimal impact on healthy tissues and reduced side effects. Newly formed blood vessels in malignant lesions exhibit chaotic growth, disordered structure, irregular shape and diameter, protrusions, and blind ends, resulting in immature vasculature; the newly formed lymphatic vessels also have aberrant structure. Structural features of the tumor vasculature determine relatively easy penetration of large molecules as well as nanometer-sized particles through a blood⁻tissue barrier and their accumulation in a tumor tissue. Also, malignant cells have altered molecular profile due to significant changes in tumor cell metabolism at every level from the genome to metabolome. Recently, the tumor interaction with cells of immune system becomes the focus of particular attention, that among others findings resulted in extensive study of cells with preferential tropism to tumor. In this review we summarize the information on the diversity of currently existing approaches to targeted drug delivery to tumor, including (i) passive targeting based on the specific features of tumor vasculature, (ii) active targeting which implies a specific binding of the antitumor agent with its molecular target, and (iii) cell-mediated tumor targeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356537PMC
January 2019

Photobiological properties of phthalocyanine photosensitizers Photosens, Holosens and Phthalosens: A comparative in vitro analysis.

J Photochem Photobiol B 2019 Feb 27;191:128-134. Epub 2018 Dec 27.

Lobachevsky State University of Nizhny Novgorod, 23 Gagarin ave., Nizhny Novgorod 603950, Russia; I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya str., Moscow 119991, Russia. Electronic address:

Photobiological properties of phthalocyanine photosensitizers, namely, clinically approved Photosens and new compounds Holosens and Phthalosens were analyzed on transitional cell carcinoma of the urinary bladder (T24) and human hepatic adenocarcinoma (SK-HEP-1). Photosens is a sulfated aluminum phthalocyanine with the number of sulfo groups 3.4, which is characterized by a high degree of hydrophilicity, slow cellular uptake, localization in lysosomes and the lowest photodynamic activity. Holosens is an octacholine zinc phthalocyanine, a cationic compound with significant charge. Holosens more efficiently enters the cells; it is localized in Golgi apparatus in addition to lysosomes and exhibits a significant inhibitory effect on cell viability upon irradiation. The highest photodynamic activity was demostrated by Phthalosens. Phthalosens is a metal-free analog of Photosens with a number of sulfo groups 2.5, which determines its amphiphilicity. Phthalosens is characterized by the highest rate of cellular uptake through the outer cell membrane, localization in cell membrane as well as in lysosomes and Golgi apparatus, and the highest activity upon irradiation among the photosensitizers studied. In general, changes in the physicochemical properties of Holosens and Phthalosens ensured an increase in their efficiency in vitro compared to Photosens. The features of accumulation, intracellular distribution and their interrelation with photodynamic activity, revealed in this work, indicate the prospects of Phthalosens and Holosens for clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphotobiol.2018.12.020DOI Listing
February 2019

3D in vitro models of tumors expressing EGFR family receptors: a potent tool for studying receptor biology and targeted drug development.

Drug Discov Today 2019 01 8;24(1):99-111. Epub 2018 Sep 8.

Institute of Biology and Biomedicine, Lobachevsky University, 23 Gagarin ave., Nizhny Novgorod 603950, Russia; I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya str., Moscow 119991, Russia. Electronic address:

Carcinomas overexpressing EGFR family receptors are of high clinical importance, because the receptors have prognostic value and are used as molecular targets for anticancer therapy. Insufficient drug efficacy necessitates further in-depth research of the receptor biology and improvement in preclinical stages of drug evaluation. Here, we review the currently used advanced 3D in vitro models of tumors, including tumor spheroids, models in natural and synthetic matrices, tumor organoids and microfluidic-based models, as a potent tool for studying EGFR biology and targeted drug development. We are especially focused on factors that affect the biology of tumor cells, causing modification in the expression and basic phosphorylation of the receptors, crosstalk with other signaling pathways and switch between downstream cascades, resulting ultimately in the resistance to antitumor agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.drudis.2018.09.003DOI Listing
January 2019

Radioactive (Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer.

Proc Natl Acad Sci U S A 2018 09 7;115(39):9690-9695. Epub 2018 Sep 7.

The Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.

We report combined therapy using upconversion nanoparticles (UCNP) coupled to two therapeutic agents: beta-emitting radionuclide yttrium-90 (Y) fractionally substituting yttrium in UCNP, and a fragment of the exotoxin A derived from genetically fused with a targeting designed ankyrin repeat protein (DARPin) specific to HER2 receptors. The resultant hybrid complex UCNP-R-T was tested using human breast adenocarcinoma cells SK-BR-3 overexpressing HER2 receptors and immunodeficient mice, bearing HER2-positive xenograft tumors. The photophysical properties of UCNPs enabled background-free imaging of the UCNP-R-T distribution in cells and animals. Specific binding and uptake of UCNP complexes in SK-BR-3 cells was observed, with separate Y- and PE40-induced cytotoxic effects characterized by IC 140 μg/mL (UCNP-R) and 5.2 μg/mL (UCNP-T), respectively. When both therapeutic agents were combined into UCNP-R-T, the synergetic effect increased markedly, ∼2200-fold, resulting in IC = 0.0024 μg/mL. The combined therapy with UCNP-R-T was demonstrated in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1809258115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166851PMC
September 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10895-018-2212-9DOI Listing
March 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.12.062DOI Listing
January 2018

Pharmacokinetics of Chlorin e₆-Cobalt Bis(Dicarbollide) Conjugate in Balb/c Mice with Engrafted Carcinoma.

Int J Mol Sci 2017 Nov 28;18(12). Epub 2017 Nov 28.

Department of Biophysics, Lobachevsky State University of Nizhny Novgorod, 23 Gagarina Av., 603950 Nizhny Novgorod, Russia.

The necessary precondition for efficient boron neutron capture therapy (BNCT) is control over the content of isotope B in the tumor and normal tissues. In the case of boron-containing porphyrins, the fluorescent part of molecule can be used for quantitative assessment of the boron content. We performed a study of the biodistribution of the chlorin ₆-Cobalt bis(dicarbollide) conjugate in carcinoma-bearing Balb/c mice using ex vivo fluorescence imaging, and developed a mathematical model describing boron accumulation and release based on the obtained experimental data. The study was performed on Balb/c tumor-bearing mice (CT-26 tumor model). A solution of the chlorin ₆-Cobalt bis(dicarbollide) conjugate (CCDC) was injected into the blood at a dose of 10 mg/kg of the animal's weight. Analysis of the fluorescence signal intensity was performed at several time points by spectrofluorimetry in blood and by laser scanning microscopy in muscle, liver, and tumor tissues. The boron content in the same samples was determined by mass spectroscopy with inductively coupled plasma. Analysis of a linear approximation between the fluorescence intensity and boron content in the tissues demonstrated a satisfactory value of approximation reliability with a Spearman's rank correlation coefficient of = 0.938, < 0.01. The dynamics of the boron concentration change in various organs, calculated on the basis of the fluorescence intensity, enabled the development of a model describing the accumulation of the studied compound and its distribution in tissues. The obtained results reveal a high level of correspondence between the model and experimental data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms18122556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751159PMC
November 2017

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphotobiol.2017.11.020DOI Listing
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbagen.2017.09.004DOI Listing
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c4tb01678eDOI Listing
February 2015

Passive and active targeting of quantum dots for whole-body fluorescence imaging of breast cancer xenografts.

J Biophotonics 2012 Nov 8;5(11-12):860-7. Epub 2012 Aug 8.

NI Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia.

Far-red and near-infrared fluorescent quantum dots (QDs) have become advancing contrast agents for efficient whole-body tumor imaging. In this study, we investigated the possibility of the vital fluorescence imaging of tumor using two contrast agents on the basis of QDs: bioinert QDs coated with polyethyleneglycol and QDs bound with anti-HER2/neu scFv antibodies. HER2/neu-positive breast cancer tumor xenografts in nude mice were used as a model. It was shown that both bioinert and tumor-targeted QD probes can be successfully applied for visualization of the tumor using in vivo imaging method, but fluorescent signal of QD-4D5scFv in tumors was considerably stronger than that of QD-PEG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbio.201200080DOI Listing
November 2012

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c0cc02842hDOI Listing
November 2010

Fluorescent immunolabeling of cancer cells by quantum dots and antibody scFv fragment.

J Biomed Opt 2009 Mar-Apr;14(2):021004

Russian Academy of Sciences, M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Ul. Miklukho-Maklaya, 16/10, 117997 GSP, Moscow V-437, Russia.

Semiconductor quantum dots (QDs) coupled with cancer-specific targeting ligands are new promising agents for fluorescent visualization of cancer cells. Human epidermal growth factor receptor 2/neu (HER2/neu), overexpressed on the surface of many cancer cells, is an important target for cancer diagnostics. Antibody scFv fragments as a targeting agent for direct delivery of fluorophores offer significant advantages over full-size antibodies due to their small size, lower cross-reactivity, and immunogenicity. We have used quantum dots linked to anti-HER2/neu 4D5 scFv antibody to label HER2/neu-overexpressing live cells. Labeling of target cells was shown to have high brightness, photostability, and specificity. The results indicate that construction based on quantum dots and scFv antibody can be successfully used for cancer cell visualization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1117/1.3122775DOI Listing
July 2009