Publications by authors named "Alexandra G Pershina"

12 Publications

  • Page 1 of 1

Smart Design of a pH-Responsive System Based on pHLIP-Modified Magnetite Nanoparticles for Tumor MRI.

ACS Appl Mater Interfaces 2021 Aug 29;13(31):36800-36815. Epub 2021 Jul 29.

Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 620108 Yekaterinburg, Russia.

Magnetic FeO nanoparticles (MNPs) are often used to design agents enhancing contrast in magnetic resonance imaging (MRI) that can be considered as one of the efficient methods for cancer diagnostics. At present, increasing the specificity of the MRI contrast agent accumulation in tumor tissues remains an open question and attracts the attention of a wide range of researchers. One of the modern methods for enhancing the efficiency of contrast agents is the use of molecules for tumor acidic microenvironment targeting, for example, pH-low insertion peptide (pHLIP). We designed novel organosilicon MNPs covered with poly(ethylene glycol) (PEG) and covalently modified by pHLIP. To study the specific features of the binding of pHLIP-modified MNPs to cells, we also obtained nanoconjugates with Cy5 fluorescent dye embedded in the SiO shell. The nanoconjugates obtained were characterized by transmission electron microscopy (TEM), attenuated total reflection (ATR), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), dynamic light scattering (DLS), UV and fluorescence spectrometry, thermogravimetric analysis (TGA), CHN elemental analyses, and vibrating sample magnetometry. Low cytotoxicity and high specificity of cellular uptake of pHLIP-modified MNPs at pH 6.4 versus 7.4 (up to 23-fold) were demonstrated in vitro. The dynamics of the nanoconjugate accumulation in the 4T1 breast cancer orthotopically grown in BALB/c mice and MDA-MB231 xenografts was evaluated in MRI experiments. Biodistribution and biocompatibility studies of the obtained nanoconjugate showed no pathological change in organs and in the blood biochemical parameters of mice after MNP administration. A high accumulation rate of pHLIP-modified MNPs in tumor compared with PEGylated MNPs after their intravenous administration was demonstrated. Thus, we propose a promising approach to design an MRI agent with the tumor acidic microenvironment targeting ability.
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http://dx.doi.org/10.1021/acsami.1c07748DOI Listing
August 2021

Tissue-Specific Ferritin- and GFP-Based Genetic Vectors Visualize Neurons by MRI in the Intact and Post-Ischemic Rat Brain.

Int J Mol Sci 2020 Nov 25;21(23). Epub 2020 Nov 25.

Laboratory of Neurobiology, Research Institute of Biology and Biophysics, Tomsk State University, 36, Lenina Ave., Tomsk 634050, Russia.

(1) Background: Neurogenesis is considered to be a potential brain repair mechanism and is enhanced in stroke. It is difficult to reconstruct the neurogenesis process only from the histological sections taken from different animals at different stages of brain damage and restoration. Study of neurogenesis would greatly benefit from development of tissue-specific visualization probes. (2) Purpose: The study aimed to explore if overexpression of ferritin, a nontoxic iron-binding protein, under a doublecortin promoter can be used for non-invasive visualization of neurogenesis using magnetic resonance imaging (MRI). (3) Methods: Ferritin heavy chain (FerrH) was expressed in the adeno-associated viral backbone (AAV) under the doublecortin promoter (pDCX), specific for young neurons, in the viral construct AAV-pDCX-FerrH. Expression of the enhanced green fluorescent protein (eGFP) was used as an expression control (AAV-pDCX-eGFP). The viral vectors or phosphate-buffered saline (PBS) were injected intracerebrally into 18 adult male Sprague-Dawley rats. Three days before injection, rats underwent transient middle-cerebral-artery occlusion or sham operation. Animals were subjected to In vivo MRI study before surgery and on days 7, 14, 21, and 28 days after injection using a Bruker BioSpec 11.7 T scanner. Brain sections obtained on day 28 after injection were immunostained for ferritin, young (DCX) and mature (NeuN) neurons, and activated microglia/macrophages (CD68). Additionally, RT-PCR was performed to confirm ferritin expression. (4) Results: T2* images in post-ischemic brains of animals injected with AAV-pDCX-FerrH showed two distinct zones of MRI signal hypointensity in the ipsilesioned hemisphere starting from 14 days after viral injection-in the ischemic lesion and near the lateral ventricle and subventricular zone (SVZ). In sham-operated animals, only one zone of hypointensity near the lateral ventricle and SVZ was revealed. Immunochemistry showed that ferritin-expressing cells in ischemic lesions were macrophages (88.1%), while ferritin-expressing cells near the lateral ventricle in animals both after ischemia and sham operation were mostly mature (55.7% and 61.8%, respectively) and young (30.6% and 7.1%, respectively) neurons. RT-PCR confirmed upregulated expression of ferritin in the caudoputamen and corpus callosum. Surprisingly, in animals injected with AAV-pDCX-eGFP we similarly observed two zones of hypointensity on T2* images. Cellular studies also showed the presence of mature (81.5%) and young neurons (6.1%) near the lateral ventricle in both postischemic and sham-operated animals, while macrophages in ischemic lesions were ferritin-positive (98.2%). (5) Conclusion: Ferritin overexpression induced by injection of AAV-pDCX-FerrH was detected by MRI using T2*-weighted images, which was confirmed by immunochemistry showing ferritin in young and mature neurons. Expression of eGFP also caused a comparable reduced MR signal intensity in T2*-weighted images. Additional studies are needed to investigate the potential and tissue-specific features of the use of eGFP and ferritin expression in MRI studies.
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http://dx.doi.org/10.3390/ijms21238951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728074PMC
November 2020

Variation in tumor pH affects pH-triggered delivery of peptide-modified magnetic nanoparticles.

Nanomedicine 2021 02 21;32:102317. Epub 2020 Oct 21.

Siberian State Medical University, Tomsk, Russia.

Acidification of the extracellular matrix, an intrinsic characteristic of many solid tumors, is widely exploited for physiologically triggered delivery of contrast agents, drugs, and nanoparticles to tumor. However, pH of tumor microenvironment shows intra- and inter-tumor variation. Herein, we investigate the impact of this variation on pH-triggered delivery of magnetic nanoparticles (MNPs) modified with pH-(low)-insertion peptide (pHLIP). Fluorescent flow cytometry, laser confocal scanning microscopy and transmission electron microscopy data proved that pHLIP-conjugated MNPs interacted with 4T1 cells in two-dimensional culture and in spheroids more effectively at pH 6.4 than at pH 7.2, and entered the cell via clathrin-independent endocytosis. The accumulation efficiency of pHLIP-conjugated MNPs in 4T1 tumors after their intravenous injection, monitored in vivo by magnetic resonance imaging, showed variation. Analysis of the tumor pH profiles recorded with implementation of original nanoprobe pH sensor, revealed obvious correlation between pH measured in the tumor with the amount of accumulated MNPs.
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http://dx.doi.org/10.1016/j.nano.2020.102317DOI Listing
February 2021

Supporting data and methods for the characterization of iron oxide nanoparticles conjugated with pH-(low)-insertion peptide, testing their cytotoxicity and analyses of biodistribution in SCID mice bearing MDA-MB231 tumor.

Data Brief 2020 Apr 31;29:105062. Epub 2019 Dec 31.

Postovsky Institute of Organic Synthesis UB RAS, 22, S. Kovalevskaya St., 620990, Yekaterinburg, Russia.

The method of FeO magnetic nanoparticle synthesis by co-precipitation, modification by 3-aminopropylsilane and conjugation with pH-(low)-insertion peptide (pHLIP) is reported. The characterization of nanoparticles by scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, elemental and thermogravimetric analyses as well as dynamic light scattering and z-potential measurements is provided. The effect of nanoparticles on the viability of mouse and human peripheral blood mononuclear cells is tested by flow cytometry. The experimental details of nanoparticle administration to tumor-bearing mice, magnetic resonance imaging scanning as well as subsequent tumor sample collection and their processing for transmission electron microscopy, inductively coupled plasma atomic emission spectroscopy, histological and immunohistochemical analyses are described. Biodistribution of the nanoparticles in mice and blood serum analysis data for experimental animals are given. The data are useful for an experiment workflow design and for the development of theranostic systems based on magnetic nanoparticles.
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http://dx.doi.org/10.1016/j.dib.2019.105062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971337PMC
April 2020

Hemozoin From the Liver Fluke, , Modulates Dendritic Cell Responses in Bronchial Asthma Patients.

Front Vet Sci 2019 16;6:332. Epub 2019 Oct 16.

Department of Microbiology, Immunology and Tropical Medicine, Research Center for Neglected Diseases of Poverty, School of Medicine & Health Sciences, George Washington University, Washington, DC, United States.

There is a general, inverse relationship between helminth infection and allergic diseases including bronchial asthma (BA). Proteins and other mediators released from parasitic worms exert cogent downmodulation of atopic and other allergic reactivity. We investigated the immune activities of an immortalized murine dendritic cell (mDC) line (JAWSII) and of primary human dendritic cells (hDCs) collected from study participants with and without BA after hemozoin (Hz) treatment. , expression of lymphocyte-activating factors-T helper 1 (Th1) induction and anti-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL-10, and IL-12β-increased significantly in mDCs pulsed with Hz. In parallel, primary dendritic cells (hDC) from cases clinically diagnosed with BA along with healthy controls were exposed to Hz in combination with lipopolysaccharide (LPS). Whereas no significant change in the cellular maturation markers, CD83, CD86, and CD40, was apparent in BA vs. healthy hDC, pulsing hDC from BA with Hz with LPS induced significant increases in expression of IL-10 and IL-12β, although not of TNF-α or tumor growth factor-beta (TGF-β). Liver fluke hemozoin Hz stimulated production of Th1 inducer and anti-inflammatory cytokines IL-10 and IL-12β from BA-hDC pulsed with Hz, an outcome that enhances our understanding of the mechanisms whereby opisthorchiasis contributes to protection against the atopic disease in liver fluke infection-endemic regions.
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http://dx.doi.org/10.3389/fvets.2019.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843058PMC
October 2019

pH-triggered delivery of magnetic nanoparticles depends on tumor volume.

Nanomedicine 2020 01 23;23:102086. Epub 2019 Aug 23.

Siberian State Medical University, Tomsk, Russia.

Nowadays there is growing recognition of the fact that biological systems have a greater impact on nanoparticle target delivery in tumors than nanoparticle design. Here we investigate the targeted delivery of FeO magnetic nanoparticles conjugated with pH-low-insertion peptide (MNP-pHLIP) on orthotopically induced MDA-MB-231 human breast carcinoma xenografts of varying volumes as a model of cancer progression. Using in vivo magnetic resonance imaging and subsequent determination of iron content in tumor samples by inductively coupled plasma atomic emission spectroscopy we found that MNP-pHLIP accumulation depends on tumor volume. Transmission electron microscopy, histological analysis and immunohistochemical staining of tumor samples suggest that blood vessel distribution is the key factor in determining the success of the accumulation of nanoparticles in tumors.
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http://dx.doi.org/10.1016/j.nano.2019.102086DOI Listing
January 2020

Imbalance in the glutathione system in Opisthorchis felineus infected liver promotes hepatic fibrosis.

Acta Trop 2019 Apr 23;192:41-48. Epub 2019 Jan 23.

Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russia.

Although data on oxidative stress during liver fluke infection have been previously presented, a comprehensive study of the glutathione system that plays a crucial role in scavenging of reactive oxygen species (ROS) and detoxification of primary and secondary oxidation products has not been addressed yet. In the present study, the hepatic glutathione system was investigated in a hamster model of experimental opisthorchiasis infection. It was shown that chronic oxidative stress in an Opisthorchis felineus infected liver, evidenced by abundant hydroperoxide accumulation, leads to strong imbalance in the hepatic glutathione system, namely the depletion of reduced form of glutathione (GSH), lowering of the GSH/GSSG ratio, and a decrease in the glutathione peroxidase and glyoxalase 1 activity. O. felineus infection provokes hepatocellular damage that results in the progression of liver fibrosis, accompanied by an increase in collagen deposition in the hepatic tissue. Modulation of hepatic GSH levels in the O. felineus infected liver through N-acetylcysteine (NAC) or l-buthionine-S, R-sulfoxinine (BSO) treatments lead to changes in expression and activity of glutathione S-transferase and glyoxalase I as well as markedly decreases or increases collagen content in the O. felineus infected liver and the severity of liver fibrosis, respectively. Thus, the glutathione system can be considered as a target for liver protection from O. felineus-induced injury.
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http://dx.doi.org/10.1016/j.actatropica.2019.01.017DOI Listing
April 2019

PMIDA-Modified FeO Magnetic Nanoparticles: Synthesis and Application for Liver MRI.

Langmuir 2018 03 6;34(11):3449-3458. Epub 2018 Mar 6.

Siberian State Medical University , 2 Moskovsky Trakt , 634050 Tomsk , Russia.

The surface modification of FeO-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 °C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r and r were 341 and 102 mmol s, respectively. The possibility of using colloidal solutions of PMIDA-modified MNPs as a T contrast agent for liver studies in vivo (at a dose of 0.6 mg kg) was demonstrated for the first time.
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http://dx.doi.org/10.1021/acs.langmuir.7b04023DOI Listing
March 2018

Production of the recombinant antimicrobial peptide UBI in Escherichia coli.

Protein Expr Purif 2018 03 21;143:38-44. Epub 2017 Oct 21.

Siberian State Medical University, 2, Moskovsky trakt, 634050 Tomsk, Russia; National Research Tomsk Polytechnic University, 30, Lenina Ave., Tomsk 634050, Russia. Electronic address:

Radiolabeled peptides derived from ubiquicidine (UBI) are of great interest for early and highly accurate scintigraphic detection and differentiation of infection and sterile inflammation. In the present work the recombinant antimicrobial peptide UBI - a fragment of the human natural cationic peptide ubiquicidine - was produced in Escherichia coli for the first time. The insoluble expression of the peptide in fusion with ketosteroid isomerase provided high yield, about 6 mg of UBI per liter. We developed an approach to produce the antimicrobial peptide UBI, that encompasses inclusion body isolation and size exclusion chromatography. This method could be the basis for industrial biotechnological production of diagnostic system components that are in high demand.
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http://dx.doi.org/10.1016/j.pep.2017.10.011DOI Listing
March 2018

Magnetic resonance imaging and spectroscopy for differential assessment of liver abnormalities induced by Opisthorchis felineus in an animal model.

PLoS Negl Trop Dis 2017 Jul 14;11(7):e0005778. Epub 2017 Jul 14.

Central Research Laboratory, Siberian State Medical University, Tomsk, Russia.

Background: European liver fluke Opisthorchis felineus, causing opisthorchiasis disease, is widespread in Russia, Ukraine, Kazakhstan and sporadically detected in the EU countries. O. felineus infection leads to hepatobiliary pathological changes, cholangitis, fibrosis and, in severe cases, malignant transformation of bile ducts. Due to absence of specific symptoms, the infection is frequently neglected for a long period. The association of opisthorchiasis with almost incurable bile duct cancer and rising international migration of people that increases the risk of the parasitic etiology of liver fibrosis in non-endemic regions determine high demand for development of approaches to opisthorchiasis detection.

Methodology/principal Findings: In vivo magnetic resonance imaging and spectroscopy (MRI and MRS) were applied for differential assessment of hepatic abnormalities induced by O. felineus in an experimental animal model. Correlations of the MR-findings with the histological data as well as the data of the biochemical analysis of liver tissue were found. MRI provides valuable information about the severity of liver impairments induced by opisthorchiasis. An MR image of O. felineus infected liver has a characteristic pattern that differs from that of closely related liver fluke infections. 1H and 31P MRS in combination with biochemical analysis data showed that O. felineus infection disturbed hepatic metabolism of the host, which was accompanied by cholesterol accumulation in the liver.

Conclusions: A non-invasive approach based on the magnetic resonance technique is very advantageous and may be successfully used not only for diagnosing and evaluating liver damage induced by O. felineus, but also for investigating metabolic changes arising in the infected organ. Since damages induced by the liver fluke take place in different liver lobes, MRI has the potential to overcome liver biopsy sampling variability that limits predictive validity of biopsy analysis for staging liver fluke-induced fibrosis.
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http://dx.doi.org/10.1371/journal.pntd.0005778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529022PMC
July 2017

3-Aminopropylsilane-modified iron oxide nanoparticles for contrast-enhanced magnetic resonance imaging of liver lesions induced by .

Int J Nanomedicine 2016;11:4451-4463. Epub 2016 Sep 6.

Siberian State Medical University.

Purpose: Liver fluke causes severe liver damage in an infected human. However, the infection often remains neglected due to the lack of pathognomonic signs. Nanoparticle-enhanced magnetic resonance imaging (MRI) offers a promising technique for detecting liver lesions induced by parasites.

Materials And Methods: Surface modification of iron oxide nanoparticles produced by coprecipitation from a solution of Fe and Fe salts using 3-aminopropylsilane (APS) was carried out. The APS-modified nanoparticles were characterized by transmission electron microscopy, fourier transform infrared spectroscopy, and thermogravimetric analysis. Magnetic resonance properties of MNPs were investigated in vitro and in vivo.

Results: The amount of APS grafted on the surface of nanoparticles (0.60±0.06 mmol g) was calculated based on elemental analysis and infrared spectroscopy data. According to transmission electron microscopy data, there were no essential changes in the structure of nanoparticles during the modification. The APS-modified nanoparticles exhibit high magnetic properties; the calculated relaxivity was 271 mmol s. To obtain suspension with optimal hydrodynamic characteristics, amino groups on the surface of nanoparticles were converted into an ionic form with HCl. Cellular uptake of modified nanoparticles by rat hepatoma cells and human monocytes in vitro was 74.1±4.5 and 10.0±3.7 pg [Fe] per cell, respectively. Low cytotoxicity of the nanoparticles was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Annexin V/7-aminoactinomycin D flow cytometry assays. For the first time, magnetic nanoparticles were applied for contrast-enhanced MRI of liver lesions induced by .

Conclusion: The synthesized APS-modified iron oxide nanoparticles showed high efficiency as an MRI contrast agent for the evaluation of opisthorchiasis-related liver damage.
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http://dx.doi.org/10.2147/IJN.S111880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019273PMC
September 2016

Hemozoin "knobs" in Opisthorchis felineus infected liver.

Parasit Vectors 2015 Sep 17;8:459. Epub 2015 Sep 17.

Siberian State Medical University, 2, Moskovsky trakt, 634050, Tomsk, Russia.

Background: Hemozoin is the pigment produced by some blood-feeding parasites. It demonstrates high diagnostic and therapeutic potential. In this work the formation of co-called hemozoin "knobs" - the bile duct ectasia filled up by hemozoin pigment - in Opisthorhis felineus infected hamster liver has been observed.

Methods: The O. felineus infected liver was examined by histological analysis and magnetic resonance imaging (MRI). The pigment hemozoin was identified by Fourier transform infrared spectroscopy and high resolution electrospray ionization mass spectrometry analysis. Hemozoin crystals were characterised by high resolution transmission electron microscopy.

Results: Hemozoin crystals produced by O. felineus have average length 403 nm and the length-to-width ratio equals 2.0. The regurgitation of hemozoin from parasitic fluke during infection leads to formation of bile duct ectasia. The active release of hemozoin from O. felineus during in vitro incubation has also been evidenced. It has been shown that the hemozoin knobs can be detected by magnetic resonance imaging.

Conclusions: In the paper for the first time the characterisation of hemozoin pigment extracted from liver fluke O. felineus has been conducted. The role of hemozoin in the modification of immune response by opisthorchiasis is assumed.
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http://dx.doi.org/10.1186/s13071-015-1061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574221PMC
September 2015
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