Publications by authors named "Alexander M Demin"

9 Publications

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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

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

L-Lysine-modified FeO nanoparticles for magnetic cell labeling.

Colloids Surf B Biointerfaces 2020 Jun 19;190:110879. Epub 2020 Feb 19.

Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 22 S. Kovalevskoy St., Yekaterinburg, 620990, Russia; Institute of Chemical Engineering, Ural Federal University, 19 Mira St., Yekaterinburg, 620002, Russia.

The efficiency of magnetic labeling with L-Lys-modified FeO magnetic nanoparticles (MNPs) and the stability of magnetization of rat adipose-derived mesenchymal stem cells, lineage-negative (Lin(-)) hematopoietic progenitor cells from mouse bone marrow and human leukemia K562 cells were studied. For this purpose, covalent modification of MNPs with 3-aminopropylsilane and N-di-Fmoc-L-lysine followed by removal of N-protecting groups was carried out. Since the degree of hydroxylation of the surface of the starting nanoparticles plays a crucial role in the silanization reaction and the possibility of obtaining stable colloidal solutions. In present work we for the first time performed a comparative qualitative and quantitative evaluation of the number of adsorbed water molecules and hydroxyl groups on the surface of chemically and physically obtained FeO MNPs using comprehensive FTIR spectroscopy and thermogravimetric analysis. The results obtained can be further used for magnetic labeling of cells in experiments in vitro and in vivo.
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http://dx.doi.org/10.1016/j.colsurfb.2020.110879DOI Listing
June 2020

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

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

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

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

Magnetic stromal layers for enhanced and unbiased recovery of co-cultured hematopoietic cells.

Anal Biochem 2016 09 16;509:146-155. Epub 2016 Jun 16.

Engelhard Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia. Electronic address:

Cell co-culture systems have a long history of application in hematology and hold promise for successful hematopoietic stem and progenitor cell expansion. Here we report that various types of stromal cells used in such co-cultures can be rapidly and efficiently labeled with l-lysine-modified Fe3O4 magnetic nanoparticles. Hematopoiesis-supporting activity does not seem to be compromised after magnetic labeling of stromal cells, and the loss of the label by stromal layers during extended culturing is negligible. Magnetic labeling allows for simple and efficient removal of stromal component, yielding unbiased hematopoietic cell populations. When Lin(-) bone mouse marrow fraction was co-cultured with magnetic stromal layers and resulting cell populations were harvested by trypsinization, the yields of total nucleated cells, colony forming cells, and phenotypically primitive Lin(-)Sca-1(+)c-kit(+) subset were substantially higher as compared with nonadherent cell fractions harvested after conventional stromal co-culture. The advantage offered by the magnetic stroma approach over the traditional one was even more significant after a second round of co-culture and was more dramatic for more primitive hematopoietic cells. We conclude that magnetic stromal layers represent a simple, efficient, and convenient tool for co-culturing and subsequent recovery of sufficiently pure unbiased populations of hematopoietic cells.
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http://dx.doi.org/10.1016/j.ab.2016.06.010DOI Listing
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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