Publications by authors named "Sergey V Vtorushin"

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.1c07748DOI Listing
August 2021

Heterogeneous Manifestations of Epithelial-Mesenchymal Plasticity of Circulating Tumor Cells in Breast Cancer Patients.

Int J Mol Sci 2021 Mar 2;22(5). Epub 2021 Mar 2.

Cancer Research Institute, Tomsk National Research Medical Center, 634050 Tomsk, Russia.

To date, there is indisputable evidence of significant CTC heterogeneity in carcinomas, in particular breast cancer. The heterogeneity of CTCs is manifested in the key characteristics of tumor cells related to metastatic progression - stemness and epithelial-mesenchymal (EMT) plasticity. It is still not clear what markers can characterize the phenomenon of EMT plasticity in the range from epithelial to mesenchymal phenotypes. In this article we examine the manifestations of EMT plasticity in the CTCs in breast cancer. The prospective study included 39 patients with invasive carcinoma of no special type. CTC phenotypes were determined by flow cytometry before any type of treatment. EMT features of CTC were assessed using antibodies against CD45, CD326 (EpCam), CD325 (N-cadherin), CK7, Snail, and Vimentin. Circulating tumor cells in breast cancer are characterized by pronounced heterogeneity of EMT manifestations. The results of the study indicate that the majority of heterogeneous CTC phenotypes (22 out of 24 detectable) exhibit epithelial-mesenchymal plasticity. The variability of EMT manifestations does not prevent intravasation. Co-expression of EpCAM and CK7, regardless of the variant of co-expression of Snail, N-cadherin, and Vimentin, are associated with a low number of CTCs. Intrapersonal heterogeneity is manifested by the detection of several CTC phenotypes in each patient. Interpersonal heterogeneity is manifested by various combinations of CTC phenotypes in patients (from 1 to 17 phenotypes).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22052504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958863PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nano.2020.102317DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nano.2019.102086DOI Listing
January 2020

Case Report: Two Cases of Cholangiocarcinoma in Patients with Infection in Western Siberia, Russian Federation.

Am J Trop Med Hyg 2019 03;100(3):599-603

University of Basel, Basel, Switzerland.

Cholangiocarcinoma (CCA) is a cancer with high mortality owing to its aggressiveness and resistance to therapy. The liver flukes of the Opisthorchiidae family have been recognized as risk factors of CCA. infection occurs in Western Siberia, the biggest endemic area in the Russian Federation, and is associated with chronic inflammation of the bile ducts, which may be linked to severe hepatobiliary morbidity. We report two cases of confirmed CCA who had a chronic infection. Both cases presented unspecific symptoms at the onset of the disease, a stage when severe pathological changes already had occurred. Both patients were living in endemic areas but did not receive any antihelminthic treatment. This report underlines the need for assessment of infection as a causative factor of CCA. The results will provide further arguments for control of in the Russian Federation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.18-0652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402895PMC
March 2019

Clinically relevant morphological structures in breast cancer represent transcriptionally distinct tumor cell populations with varied degrees of epithelial-mesenchymal transition and CD44CD24 stemness.

Oncotarget 2017 Sep 19;8(37):61163-61180. Epub 2017 May 19.

Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050, Tomsk, Russian Federation.

Intratumor morphological heterogeneity in breast cancer is represented by different morphological structures (tubular, alveolar, solid, trabecular, and discrete) and contributes to poor prognosis; however, the mechanisms involved remain unclear. In this study, we performed 3D imaging, laser microdissection-assisted array comparative genomic hybridization and gene expression microarray analysis of different morphological structures and examined their association with the standard immunohistochemistry scorings and CD44CD24 cancer stem cells. We found that the intratumor morphological heterogeneity is not associated with chromosomal aberrations. By contrast, morphological structures were characterized by specific gene expression profiles and signaling pathways and significantly differed in progesterone receptor and Ki-67 expression. Most importantly, we observed significant differences between structures in the number of expressed genes of the epithelial and mesenchymal phenotypes and the association with cancer invasion pathways. Tubular (tube-shaped) and alveolar (spheroid-shaped) structures were transcriptionally similar and demonstrated co-expression of epithelial and mesenchymal markers. Solid (large shapeless) structures retained epithelial features but demonstrated an increase in mesenchymal traits and collective cell migration hallmarks. Mesenchymal genes and cancer invasion pathways, as well as Ki-67 expression, were enriched in trabecular (one/two rows of tumor cells) and discrete groups (single cells and/or arrangements of 2-5 cells). Surprisingly, the number of CD44CD24 cells was found to be the lowest in discrete groups and the highest in alveolar and solid structures. Overall, our findings indicate the association of intratumor morphological heterogeneity in breast cancer with the epithelial-mesenchymal transition and CD44CD24 stemness and the appeal of this heterogeneity as a model for the study of cancer invasion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617414PMC
September 2017

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0005778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529022PMC
July 2017

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13071-015-1061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574221PMC
September 2015

Intratumoral morphological heterogeneity of breast cancer: neoadjuvant chemotherapy efficiency and multidrug resistance gene expression.

Sci Rep 2014 Apr 16;4:4709. Epub 2014 Apr 16.

1] Department of Experimental Oncology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russian Federation [2] Laboratory of Translational Cell and Molecular Biomedicine, Tomsk State University, Tomsk, Russian Federation [3] Department of Oncology, Siberian State Medical University, Tomsk, Russian Federation.

In this study, the influence of intratumoral morphological heterogeneity of breast cancer on neoadjuvant chemotherapy (NAC) efficiency was investigated. In particular, we analysed the association of NAC response and pre- and post-NAC expression of the main multidrug resistance (MDR) genes--ABCB1, ABCC1, ABCC5, ABCG1, and ABCG2, with the presence of different morphological structures in breast tumors. In addition, the expression of MDR genes was investigated in different morphological structures and in their microenvironment by comparing probes obtained using laser microdissection. The results of this study showed that tumors with alveolar structures were more frequently NAC-nonresponsive than cases without this structural type (p = 0.0028, Bonferroni-corrected p = 0.014). The presence of trabecular structures in breast tumors was also associated with chemoresistance (p = 0.0272, Bonferroni-corrected p = 0.136). High expression of MDR genes was not found in alveolar structures (including their microenvironment) and in tumors containing this structural type. In contrast, more active MDR genes and expression of the ABCB1 gene were found only in trabecular structures. Taken together, our data indicate that breast tumors with alveolar structures possess resistance to NAC, which is not related to high expression of MDR genes, whereas chemoresistance of tumors with trabecular structures can depend on the expression level of ABCB1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep04709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988480PMC
April 2014

Phenotypic drift as a cause for intratumoral morphological heterogeneity of invasive ductal breast carcinoma not otherwise specified.

Biores Open Access 2013 Apr;2(2):148-54

Department of Pathological Anatomy and Cytology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences , Tomsk, Russian Federation. ; Department of Pathological Anatomy, Siberian State Medical University , Tomsk, Russian Federation.

Invasive ductal carcinoma (IDC) not otherwise specified (NOS), the most common type of breast cancer, demonstrates great intratumoral morphological heterogeneity, which encompasses the presence of different types of morphological structures-tubular, trabecular, solid, and alveolar structures and discrete groups of tumor cells, the origins of which remain unclear at present. In this study of 162 IDC NOS patients, we investigated whether the distribution of different types of morphological structures is related to the basic clinicopathological parameters of IDC NOS. Our results showed that in patients with only one type of tumor structure, the presence of any one of the five types was equally probable; however, cases with two types of structures were more likely to contain trabecular structures than the other four types. The development of intratumoral morphological heterogeneity was not associated with menopausal status, tumor size, histological grade, hematogenic metastasis, or recurrence. However, the number of different types of morphological structures was significantly higher in luminal tumors than in triple-negative tumors. An increase in the frequency of lymph node metastasis correlated with the increased number of different types of structures in breast tumors; however, in contrast to premenopausal patients, this association was explained by the presence of alveolar structures in postmenopausal women. In addition, we showed a significant decrease in the numbers of positive lymph nodes in tumors with high numbers of morphological variants. The frequency of lymph node metastases and the number of positive nodes were generally independent features and formed by different mechanisms. Based on the evidence, the term "phenotypic drift" has been designated as the basis for the development of intratumoral morphological heterogeneity of IDC NOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/biores.2012.0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620470PMC
April 2013

Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response.

Cancer Chemother Pharmacol 2013 Jan 2;71(1):153-63. Epub 2012 Oct 2.

Department of Experimental Oncology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russian Federation.

Purpose: We aimed to examine the association between alterations in multidrug resistance (MDR) gene expression, measured before and after neoadjuvant chemotherapy (NAC), and short-term response in a cohort of stage IIA-IIIC breast cancer patients (n = 84).

Methods: All patients were treated with two to four preoperative cycles of FAC (5-fluorouracil-adriamycin-cyclophosphamide), CAX (cyclophosphamide-adriamycin-xeloda) or taxane regimes. The expression levels of key MDR genes (ABCB1, ABCC1, ABCC2, ABCC3, ABCC5, ABCG1, ABCG2, GSTP1, and MVP) were evaluated in both tumor tissues obtained pre-therapy and in specimens removed by final surgery, using TaqMan-based quantitative reverse transcriptase PCR.

Results: No significant difference in the average level of MDR gene expression in paired breast tumors before and after NAC was found when analyzed in both responsive and non-responsive patients. There was no correlation between the expression levels of MDR genes in pre-NAC tumors and immediate NAC response. In the group with tumor responses, we found a statistically significant downregulation of expression of ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2, GSTP1, and MVP genes following NAC in FAC and CAX-treated patients (67-93% of cases). In contrast, we found that expression of these genes was upregulated after NAC, mostly in non-responsive patients (55-96% of cases). Responsiveness to taxotere was related to reduced levels of ABCB1, ABCC2, ABCG1, ABCG2, and MVP mRNA in tumor samples collected after chemotherapy.

Conclusion: Our results suggest that reductions in MDR gene expression in post-NAC samples in comparison with pre-NAC are associated with tumor response to FAC and CAX as well as taxotere-based NAC, while patients displaying MDR gene upregulation had resistance to therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-012-1992-xDOI Listing
January 2013
-->