202 results on '"V. Shuvaev"'
Search Results
2. Physiologically based modeling of LNP-mediated delivery of mRNA in the vascular system
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Hamideh Parhiz, Vladimir V. Shuvaev, Qin Li, Tyler E. Papp, Awurama A. Akyianu, Ruiqi Shi, Amir Yadegari, Hamna Shahnawaz, Sean C. Semple, Barbara L. Mui, Drew Weissman, Vladimir R. Muzykantov, and Patrick M. Glassman
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MT: Delivery Strategies ,mRNA ,lipid nanoparticles ,nucleic acid delivery ,drug targeting ,pharmacokinetics ,Therapeutics. Pharmacology ,RM1-950 - Abstract
RNA therapeutics are an emerging, powerful class of drugs with potential applications in a wide range of disorders. A central challenge in their development is the lack of clear pharmacokinetic (PK)-pharmacodynamic relationship, in part due to the significant delay between the kinetics of RNA delivery and the onset of pharmacologic response. To bridge this gap, we have developed a physiologically based PK/pharmacodynamic model for systemically administered mRNA-containing lipid nanoparticles (LNPs) in mice. This model accounts for the physiologic determinants of mRNA delivery, active targeting in the vasculature, and differential transgene expression based on nanoparticle coating. The model was able to well-characterize the blood and tissue PKs of LNPs, as well as the kinetics of tissue luciferase expression measured by ex vivo activity in organ homogenates and bioluminescence imaging in intact organs. The predictive capabilities of the model were validated using a formulation targeted to intercellular adhesion molecule-1 and the model predicted nanoparticle delivery and luciferase expression within a 2-fold error for all organs. This modeling platform represents an initial strategy that can be expanded upon and utilized to predict the in vivo behavior of RNA-containing LNPs developed for an array of conditions and across species.
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- 2024
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3. Engineered Dual Antioxidant Enzyme Complexes Targeting ICAM-1 on Brain Endothelium Reduce Brain Injury-Associated Neuroinflammation
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Brian M. Leonard, Vladimir V. Shuvaev, Trent A. Bullock, Kalpani N. Udeni Galpayage Dona, Vladimir R. Muzykantov, Allison M. Andrews, and Servio H. Ramirez
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traumatic brain injury ,neuroinflammation ,brain vasculature ,blood–brain barrier ,nanomedicine ,superoxide dismutase 1 ,Technology ,Biology (General) ,QH301-705.5 - Abstract
The neuroinflammatory cascade triggered by traumatic brain injury (TBI) represents a clinically important point for therapeutic intervention. Neuroinflammation generates oxidative stress in the form of high-energy reactive oxygen and nitrogen species, which are key mediators of TBI pathology. The role of the blood–brain barrier (BBB) is essential for proper neuronal function and is vulnerable to oxidative stress. Results herein explore the notion that attenuating oxidative stress at the vasculature after TBI may result in improved BBB integrity and neuroprotection. Utilizing amino-chemistry, a biological construct (designated “dual conjugate” for short) was generated by covalently binding two antioxidant enzymes (superoxide dismutase 1 (SOD-1) and catalase (CAT)) to antibodies specific for ICAM-1. Bioengineering of the conjugate preserved its targeting and enzymatic functions, as evaluated by real-time bioenergetic measurements (via the Seahorse-XF platform), in brain endothelial cells exposed to increasing concentrations of hydrogen peroxide or a superoxide anion donor. Results showed that the dual conjugate effectively mitigated the mitochondrial stress due to oxidative damage. Furthermore, dual conjugate administration also improved BBB and endothelial protection under oxidative insult in an in vitro model of TBI utilizing a software-controlled stretching device that induces a 20% in mechanical strain on the endothelial cells. Additionally, the dual conjugate was also effective in reducing indices of neuroinflammation in a controlled cortical impact (CCI)-TBI animal model. Thus, these studies provide proof of concept that targeted dual antioxidant biologicals may offer a means to regulate oxidative stress-associated cellular damage during neurotrauma.
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- 2024
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4. Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases
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Laura T. Ferguson, Xiaonan Ma, Jacob W. Myerson, Jichuan Wu, Patrick M. Glassman, Marco E. Zamora, Elizabeth D. Hood, Michael Zaleski, Mengwen Shen, Eno-Obong Essien, Vladimir V. Shuvaev, and Jacob S. Brenner
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inhaled ,nanomedicine ,nintedanib ,pulmonary fibrosis ,surfactant ,Biotechnology ,TP248.13-248.65 ,Medical technology ,R855-855.5 - Abstract
Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano‐scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000‐fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as “drug depots.” After deposition in the surfactant layer, liposomes are transferred over 3–6 h to alveolar leukocytes (which take up a surprisingly minor 1–5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.
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- 2023
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5. Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)
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Ralph A. Pietrofesa, Kyewon Park, Om P. Mishra, Darrah Johnson-McDaniel, Jacob W. Myerson, Vladimir V. Shuvaev, Evguenia Arguiri, Shampa Chatterjee, Ganesh S. Moorthy, Athena Zuppa, Wei-Ting Hwang, and Melpo Christofidou-Solomidou
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active chlorine species ,chlorination damage ,copper oxide ,inflammation ,LGM2605 ,myeloperoxidase ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.
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- 2021
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6. Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium
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Luca Goitre, Peter V. DiStefano, Andrea Moglia, Nicholas Nobiletti, Eva Baldini, Lorenza Trabalzini, Julie Keubel, Eliana Trapani, Vladimir V. Shuvaev, Vladimir R. Muzykantov, Ingrid H. Sarelius, Saverio Francesco Retta, and Angela J. Glading
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Medicine ,Science - Abstract
Abstract The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subsequent deficit in barrier function remains undefined. Previous studies have shown that loss of KRIT1 increases the production of reactive oxygen species (ROS) and exacerbates vascular permeability triggered by several inflammatory stimuli, but not TNF−α. We now show that endothelial ROS production directly contributes to the loss of barrier function in KRIT1 deficient animals and cells, as targeted antioxidant enzymes reversed the increase in permeability in KRIT1 heterozygous mice as shown by intravital microscopy. Rescue of the redox state restored responsiveness to TNF-α in KRIT1 deficient arterioles, but not venules. In vitro, KRIT1 depletion increased endothelial ROS production via NADPH oxidase signaling, up-regulated Nox4 expression, and promoted NF-κB dependent promoter activity. Recombinant yeast avenanthramide I, an antioxidant and inhibitor of NF-κB signaling, rescued barrier function in KRIT1 deficient cells. However, KRIT1 depletion blunted ROS production in response to TNF-α. Together, our data indicate that ROS signaling is critical for the loss of barrier function following genetic deletion of KRIT1.
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- 2017
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7. Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury
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Evan M. Lutton, Roshanak Razmpour, Allison M. Andrews, Lee Anne Cannella, Young-Jin Son, Vladimir V. Shuvaev, Vladimir R. Muzykantov, and Servio H. Ramirez
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Medicine ,Science - Abstract
Abstract Traumatic brain injury (TBI) contributes to one third of injury related deaths in the US. Treatment strategies for TBI are supportive, and the pathophysiology is not fully understood. Secondary mechanisms of injury in TBI, such as oxidative stress and inflammation, are points at which intervention may reduce neuropathology. Evidence suggests that reactive oxygen species (ROS) propagate blood-brain barrier (BBB) hyperpermeability and inflammation following TBI. We hypothesized that targeted detoxification of ROS may improve the pathological outcomes of TBI. Following TBI, endothelial activation results in a time dependent increase in vascular expression of ICAM-1. We conjugated catalase to anti-ICAM-1 antibodies and administered the conjugate to 8 wk old C57BL/6J mice 30 min after moderate controlled cortical impact injury. Results indicate that catalase targeted to ICAM-1 reduces markers of oxidative stress, preserves BBB permeability, and attenuates neuropathological indices more effectively than non-targeted catalase and anti-ICAM-1 antibody alone. Furthermore, the study of microglia by two-photon microscopy revealed that anti-ICAM-1/catalase prevents the transition of microglia to an activated phenotype. These findings demonstrate the use of a targeted antioxidant enzyme to interfere with oxidative stress mechanisms in TBI and provide a proof-of-concept approach to improve acute TBI management that may also be applicable to other neuroinflammatory conditions.
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- 2017
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8. Endothelial Targeted Strategies to Combat Oxidative Stress: Improving Outcomes in Traumatic Brain Injury
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Evan M. Lutton, S. Katie Farney, Allison M. Andrews, Vladimir V. Shuvaev, Gwo-Yu Chuang, Vladimir R. Muzykantov, and Servio H. Ramirez
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traumatic brain injury ,oxidative stress ,catalase ,blood-brain barrier ,nanomedicine ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The endothelium is a thin monolayer of specialized cells that lines the luminal wall of blood vessels and constitutes the critical innermost portion of the physical barrier between the blood and the brain termed the blood-brain barrier (BBB). Aberrant changes in the endothelium occur in many neuropathological states, including those with high morbidity and mortality that lack targeted therapeutic interventions, such as traumatic brain injury (TBI). Utilizing ligands of surface determinants expressed on brain endothelium to target and combat injury mechanisms at damaged endothelium offers a new approach to the study of TBI and new avenues for clinical advancement. Many factors influence the targets that are expressed on endothelium. Therefore, the optimization of binding sites and ideal design features of nanocarriers are controllable factors that permit the engineering of nanotherapeutic agents with applicability that is specific to a known disease state. Following TBI, damaged endothelial cells upregulate cell adhesion molecules, including ICAM-1, and are key sites of reactive oxygen species (ROS) generation, including hydrogen peroxide. Reactive oxygen species along with pro-inflammatory mediators are known to contribute to endothelial damage and loss of BBB integrity. The use of targeted endothelial nanomedicine, with conjugates of the antioxidant enzyme catalase linked to anti-ICAM-1 antibodies, has recently been demonstrated to minimize oxidative stress at the BBB and reduce neuropathological outcomes following TBI. Here, we discuss targeted endothelial nanomedicine and its potential to provide benefits in TBI outcomes and future directions of this approach.
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- 2019
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9. Maple Information Tools in the Study of Mathematical Logic Questions
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A. A. Olenev, E. M. Petlina, A. V. Shuvaev, N. V. Grivennaya, and A. N. Khabarov
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- 2023
10. Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE)
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Hamideh Parhiz, Jacob S. Brenner, Priyal N. Patel, Tyler E. Papp, Hamna Shahnawaz, Qin Li, Ruiqi Shi, Marco E. Zamora, Amir Yadegari, Oscar A. Marcos-Contreras, Ambika Natesan, Norbert Pardi, Vladimir V. Shuvaev, Raisa Kiseleva, Jacob W. Myerson, Thomas Uhler, Rachel S. Riley, Xuexiang Han, Michael J. Mitchell, Kieu Lam, James Heyes, Drew Weissman, and Vladimir R. Muzykantov
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Inflammation ,Lipopolysaccharides ,Toxicity ,SARS-CoV-2 ,mRNA ,Lipid nanoparticle ,COVID-19 ,Pharmaceutical Science ,Adverse effect ,Article ,Mice ,Nanoparticle ,Liposomes ,Animals ,Humans ,Nanoparticles ,RNA, Messenger ,Pandemics - Abstract
Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs to deliver therapeutic proteins or vaccinate against infectious diseases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg−1, or intravenously (IV), 2 mg kg−1, and then IV administer modmRNA-LNP, 0.32 mg kg−1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver by 95-fold and 52-fold, respectively. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion and TLR3 −/− and TLR4−/− knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed., Graphical abstract Unlabelled Image
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- 2022
11. Radiation pollution as a threat to the environmental security of the Russia
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E. A. Sharyapova, A. V. Shuvaev, and I. O. Zhavoronkova
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The topic of the article is relevant — the problem of radioactive waste management, since the task of increasing the level of security of organizations of the country’s nuclear power-industrial complexes is one of the priorities for ensuring state and public security in the National Security Strategy of the Russian Federation. The growth of radioactive waste is a hazard to human health and the environment. The state needs a unified regulation of the radioactive waste management policy and prevention of radioactive disasters.
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- 2022
12. Formation of a mechanism for assigning trust and differentiating access rights to information resources of an enterprise
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A. M. Troshkov, M. A. Troshkov, A. N. Ermakova, S. V. Bogdanova, and A. V. Shuvaev
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General Engineering - Published
- 2022
13. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding
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Carla Riera-Domingo, Eduarda Leite-Gomes, Iris Charatsidou, Peihua Zhao, Giovanna Carrá, Federica Cappellesso, Larissa Mourao, Maxim De Schepper, Dana Liu, Jens Serneels, Mohamad-Gabriel Alameh, Vladimir V. Shuvaev, Tatjana Geukens, Edoardo Isnaldi, Hans Prenen, Drew Weissman, Vladimir R. Muzykantov, Stefaan Soenen, Christine Desmedt, Colinda L. G. J. Scheele, Anna Sablina, Mario Di Matteo, Rosa Martín-Pérez, and Massimiliano Mazzone
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TNF-Related Apoptosis-Inducing Ligand ,Receptors, TNF-Related Apoptosis-Inducing Ligand ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Endothelial Cells ,Humans ,Breast Neoplasms ,Apoptosis ,Female ,Human medicine ,Ligands - Abstract
Endothelial cells (ECs) grant access of disseminated cancer cells to distant organs. However, the molecular players regulating the activation of quiescent ECs at the premetastatic niche (PMN) remain elusive. Here, we find that ECs at the PMN coexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5). Unexpectedly, endothelial TRAIL interacts intracellularly with DR5 to prevent its signaling and preserve a quiescent vascular phenotype. In absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB/p38-dependent EC stickiness, compromising vascular integrity and promoting myeloid cell infiltration, breast cancer cell adhesion, and metastasis. Consistently, both down-regulation of endothelial TRAIL at the PMN by proangiogenic tumor-secreted factors and the presence of the endogenous TRAIL inhibitors decoy receptor 1 (DcR1) and DcR2 favor metastasis. This study discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination. ispartof: SCIENCE ADVANCES vol:9 issue:12 ispartof: location:United States status: published
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- 2023
14. A new method for monitoring wells productivity index dynamics
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V. Yu. Klimov, S. А. Shmidt, I. Ya. Edelman, S.I. Gabitova, D. V. Shuvaev, and L. A. Davletbakova
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geography ,Index (economics) ,geography.geographical_feature_category ,Polymers and Plastics ,Environmental science ,Agricultural engineering ,Business and International Management ,Productivity ,Industrial and Manufacturing Engineering ,Water well - Abstract
А method for monitoring wells productivity index dynamics from the moment of its start-ups is proposed. It allows detecting candidates for conducting well tests (WT) and well interventions for the increase of a daily production. The method is based on an integral analysis using pressure maps and well tests. Application of this method on the Salym group of oilfields has allowed concluding about wells stock status, about productivity index dynamics in time, also to make an assumption about the reasons for its change. The analysis showed that productivity index relative changes in horizontal wells lower than in slanted wells.
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- 2021
15. Mechanism of Collaborative Enhancement of Binding of Paired Antibodies to Distinct Epitopes of Platelet Endothelial Cell Adhesion Molecule-1.
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Raisa Kiseleva, Colin F Greineder, Carlos H Villa, Elizabeth D Hood, Vladimir V Shuvaev, Jing Sun, Ann-Marie Chacko, Valsamma Abraham, Horace M DeLisser, and Vladimir R Muzykantov
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Medicine ,Science - Abstract
Monoclonal antibodies (mAbs) directed to extracellular epitopes of human and mouse Platelet Endothelial Cell Adhesion Molecule-1 (CD31 or PECAM-1) stimulate binding of other mAbs to distinct adjacent PECAM-1 epitopes. This effect, dubbed Collaborative Enhancement of Paired Affinity Ligands, or CEPAL, has been shown to enhance delivery of mAb-targeted drugs and nanoparticles to the vascular endothelium. Here we report new insights into the mechanism underlying this effect, which demonstrates equivalent amplitude in the following models: i) cells expressing a full length PECAM-1 and mutant form of PECAM-1 unable to form homodimers; ii) isolated fractions of cellular membranes; and, iii) immobilized recombinant PECAM-1. These results indicate that CEPAL is mediated not by interference in cellular functions or homophilic PECAM-1 interactions, but rather by conformational changes within the cell adhesion molecule induced by ligand binding. This mechanism, mediated by exposure of partially occult epitopes, is likely to occur in molecules other than PECAM-1 and may represent a generalizable phenomenon with valuable practical applications.
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- 2017
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16. Classification of residual recoverable and non-recoverable oil reserves by the reservoir complexity index (RCI)
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V. Yu. Klimov, B. V. Malyshev, and D. V. Shuvaev
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Complexity index ,Polymers and Plastics ,Petroleum engineering ,Oil reserves ,Environmental science ,Business and International Management ,Residual ,Industrial and Manufacturing Engineering - Abstract
The paper considers a new engineering analytical tool for express oil reserves assessment. Proposed method is based on classifying oil reserves by complexity – reservoir complexity index (RCI). It allows to optimize the development system and form a well interventions program. The method is suggested to use three main parameters for development complexity estimation: reservoir permeability, start watercut (which contains the parameters of the curve of relative permeability, saturation and viscosity) and geological heterogeneity (pattern efficiency). An economic estimation of the well profitability is carried out by calculating PV UDC indicator (unit development cost, CAPEX / total oil production). The advantages of this indicator is that it allows to determine the economic attractiveness and does not require macro parameters and costs for the building well pads Due to the economic assessment and well ranking, it is possible to obtain profitable well pads and select candidates for sidetracking. The novelty of the work lies in the use of an updated methodology for the reservoir complexity index estimation for the remaining recoverable reserves classification. As a result, high-quality tool is created that integrates RCI and economic model. It is aimed for solving reservoir engineering problems and increasing the project cost The proposed method can be applied to other fields with minor modifications.
- Published
- 2021
17. Dual Affinity to RBCs and Target Cells (DART) enhances both organ- and cell type-targeting of intravascular nanocarriers
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Laura T. Ferguson, Elizabeth D. Hood, Tea Shuvaeva, Vladimir V. Shuvaev, Maria C. Basil, Zhicheng Wang, Jia Nong, Xiaonan Ma, Jichuan Wu, Jacob W. Myerson, Oscar A. Marcos-Contreras, Jeremy Katzen, Justine M. Carl, Edward E. Morrisey, Edward Cantu, Carlos H. Villa, Samir Mitragotri, Vladimir R. Muzykantov, and Jacob S. Brenner
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Drug Carriers ,Mice ,Drug Delivery Systems ,Erythrocytes ,Pharmaceutical Preparations ,General Engineering ,General Physics and Astronomy ,Animals ,Endothelial Cells ,Nanoparticles ,General Materials Science ,Lung ,Article - Abstract
A long-standing goal of nanomedicine is to improve a drug’s benefit by loading it into a nanocarrier that homes solely to a specific target cell and organ. Unfortunately, nanocarriers usually end up with only a small percentage of the injected dose (% ID) in the target organ, due largely to clearance by the liver and spleen. Further, cell-type-specific targeting is rarely achieved without reducing target organ accumulation. To solve these problems, we introduce DART (dual affinity to RBCs and target cells), in which nanocarriers are conjugated to two affinity ligands, one binding red blood cells, and one binding a target cell (here, pulmonary endothelial cells). DART nanocarriers first bind red blood cells, then transfer to the target organ’s endothelial cells as the bound red blood cells squeeze through capillaries. We show that within minutes after intravascular injection in mice, nearly 70 % ID of DART nanocarriers accumulate in the target organ (lungs), more than doubling the % ID ceiling achieved by a multitude of prior technologies, finally achieving a majority % ID in a target organ. Humanized DART nanocarriers in ex vivo perfused human lungs recapitulate this phenomenon. Furthermore, DART enhances the selectivity of delivery to target endothelial cells over local phagocytes within the target organ by 6-fold. DART’s marked improvement in both organ- and cell-type targeting may thus be helpful in localizing drugs for a multitude of medical applications.
- Published
- 2022
18. A NEW METHOD OF DECLINE CURVE FORECASTING FOR PROJECT WELLS ON THE BASE OF MACHINE LEARNING ALGORITHMS
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S.I. Gabitova, L. A. Davletbakova, I. Ya. Edelman, V. Yu. Klimov, S. А. Shmidt, and D. V. Shuvaev
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Computer science ,business.industry ,Artificial intelligence ,Machine learning ,computer.software_genre ,business ,Base (topology) ,computer - Abstract
The article describes new decline curves (DC) forecasting method for project wells. The method is based on the integration of manual grouping of DC and machine learning (ML) algorithms appliance. ML allows finding hidden connections between features and the output. Article includes the decline curves analysis of two well completion types: horizontal and slanted wells, which illustrates that horizontal wells are more effective than slanted.
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- 2020
19. Designing a Digital Information Service for the Automated Workstation of an AIC (Agro-Industrial Complex)-Specialist
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Alexander M. Troshkov, Anna N. Ermakova, Svetlana V. Bogdanova, Alexander V. Shuvaev, and Svetlana A. Molchanenko
- Published
- 2022
20. Copper Oxide Nanoparticle-Induced Acute Inflammatory Response and Injury in Murine Lung Is Ameliorated by Synthetic Secoisolariciresinol Diglucoside (LGM2605)
- Author
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Kyewon Park, Shampa Chatterjee, Vladimir V. Shuvaev, Wei-Ting Hwang, Melpo Christofidou-Solomidou, Ganesh S. Moorthy, Evguenia Arguiri, Jacob W. Myerson, Om P. Mishra, Darrah Johnson-McDaniel, Athena F. Zuppa, and Ralph A. Pietrofesa
- Subjects
Inflammasomes ,Metal Nanoparticles ,Pharmacology ,medicine.disease_cause ,Mice ,Glucosides ,oxidative stress ,Biology (General) ,Butylene Glycols ,Lung ,chlorination damage ,Spectroscopy ,active chlorine species ,chemistry.chemical_classification ,biology ,Oxides ,ROS ,General Medicine ,Computer Science Applications ,Chemistry ,myeloperoxidase ,Myeloperoxidase ,Toxicity ,Female ,LGM2605 ,medicine.symptom ,Chlorine ,Bronchoalveolar Lavage Fluid ,QH301-705.5 ,DNA damage ,Inflammation ,Catalysis ,Article ,secoisolariciresinol diglucoside ,Inorganic Chemistry ,medicine ,Animals ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Cell damage ,Peroxidase ,Reactive oxygen species ,Organic Chemistry ,medicine.disease ,copper oxide ,Mice, Inbred C57BL ,chemistry ,Nanotoxicology ,inflammation ,biology.protein ,nanoparticles ,Reactive Oxygen Species ,Oxidative stress ,Copper ,DNA Damage - Abstract
Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.
- Published
- 2021
- Full Text
- View/download PDF
21. Social Network Valuation Using the Discounting Cash Flow Method
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A. V. Shuvaev, A. F. Dolgopolova, K. V. Yupatova, Oleg Malafeyev, Tatyana G. Gurnovich, and Irina Zaitseva
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Microeconomics ,Discounting ,Social network ,business.industry ,Economics ,Information technology ,Cost accounting ,Cash flow ,business ,Income approach ,Valuation (finance) - Abstract
Social networks are different from traditional companies, therefore, the article discusses the methodology of social networks valuation is considered, as well as the features arising by the specifics of the activities of such companies. The results are interpreted and the conclusions are made regarding the accuracy of social network valuation by discounting cash flows of the company.
- Published
- 2021
22. Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial Marker
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Vladimir V. Shuvaev, Kelsey G. DeFrates, Olivia M. McPherson, Vladimir R. Muzykantov, Jenna H Towslee, David M. Eckmann, Russell J. Composto, Bruce Braender, Jacob W. Myerson, and Oscar A. Marcos-Contreras
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Steric effects ,Surface Properties ,Nanogels ,General Physics and Astronomy ,02 engineering and technology ,Conjugated system ,Caveolae ,Microscopy, Atomic Force ,010402 general chemistry ,01 natural sciences ,Article ,chemistry.chemical_compound ,Elastic Modulus ,Animals ,Humans ,General Materials Science ,Ethylenedioxy ,General Engineering ,Membrane Proteins ,Adhesion ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,chemistry ,Targeted drug delivery ,Biophysics ,Nanoparticles ,Polystyrene ,Nanocarriers ,0210 nano-technology ,Nanogel - Abstract
Deformability of injectable nanocarriers impacts rheological behavior, drug loading, and affinity target adhesion. Here, we present atomic force microscopy (AFM) and spectroscopy measurements of nanocarrier Young's moduli, tune the moduli of deformable nanocarriers with cross-linkers, and demonstrate vascular targeting behavior that correlates with Young's modulus. Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs). Single particle-scale AFM measurements determined NG moduli varying from ∼50-150 kPa for unmodified NGs or NGs with a short hydrophilic cross-linker (2,2'-(ethylenedioxy)bis(ethylamine), EOD) to ∼350 kPa for NGs modified with a longer hydrophilic cross-linker (4,9-dioxa-1,12-dodecanediamine, DODD) to ∼10 MPa for NGs modified with a longer hydrophobic cross-linker (1,12-diaminododecane, DAD). Cross-linked NGs were conjugated to antibodies for plasmalemma vesicle associated protein (PLVAP), a caveolar endothelial marker that cannot be accessed by rigid particles larger than ∼100 nm. In previous work, 150 nm NGs effectively targeted PLVAP, where rigid particles of similar diameter did not. EOD-modified NGs targeted PLVAP less effectively than unmodified NGs, but more effectively than DODD or DAD modified NGs, which both yielded low levels of targeting, resembling results previously obtained with polystyrene particles. Cross-linked NGs were also conjugated to antibodies against intracellular adhesion molecule-1 (ICAM-1), an endothelial marker accessible to large rigid particles. Cross-linked NGs and unmodified NGs targeted uniformly to ICAM-1. We thus demonstrate cross-linker modification of NGs, AFM determination of NG mechanical properties varying with cross-linker, and tuning of specific sterically constrained vascular targeting behavior in correlation with cross-linker-modified NG mechanical properties.
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- 2019
23. Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae
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Radu V. Stan, Vladimir V. Shuvaev, Melpo Christofidou-Solomidou, Vladimir R. Muzykantov, Jasmina C. Cheung-Lau, Katherine W. Pulsipher, Ivan J. Dmochowski, Raisa Yu Kiseleva, Kathleen M. LeFort, Evguenia Arguiri, and Makan Khoshnejad
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Male ,0301 basic medicine ,Immunoconjugates ,Endosome ,Archaeal Proteins ,media_common.quotation_subject ,Biophysics ,Bioengineering ,02 engineering and technology ,Caveolae ,Article ,Cell Line ,Biomaterials ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,Animals ,Internalization ,media_common ,Drug Carriers ,biology ,Superoxide Dismutase ,Superoxide ,Vesicle ,021001 nanoscience & nanotechnology ,Cell biology ,Mice, Inbred C57BL ,Ferritin ,030104 developmental biology ,chemistry ,Mechanics of Materials ,Archaeoglobus fulgidus ,Ferritins ,Ceramics and Composites ,biology.protein ,Nanoparticles ,Nanomedicine ,Nanocarriers ,0210 nano-technology - Abstract
One of the goals of nanomedicine is targeted delivery of therapeutic enzymes to the sub-cellular compartments where their action is needed. Endothelial caveolae-derived endosomes represent an important yet challenging destination for targeting, in part due to smaller size of the entry aperture of caveolae (ca. 30–50 nm). Here, we designed modular, multi-molecular, ferritin-based nanocarriers with uniform size (20 nm diameter) for easy drug-loading and targeted delivery of enzymatic cargo to these specific vesicles. These nanocarriers targeted to caveolar Plasmalemmal Vesicle-Associated Protein (Plvap) deliver superoxide dismutase (SOD) into endosomes in endothelial cells, the specific site of influx of superoxide mediating by such pro-inflammatory signaling as some cytokines and lipopolysaccharide (LPS). Cell studies showed efficient internalization of Plvap-targeted SOD-loaded nanocarriers followed by dissociation from caveolin-containing vesicles and intracellular transport to endosomes. The nanocarriers had a profound protective anti-inflammatory effect in an animal model of LPS-induced inflammation, in agreement with the characteristics of their endothelial uptake and intracellular transport, indicating that these novel, targeted nanocarriers provide an advantageous platform for caveolae-dependent delivery of biotherapeutics.
- Published
- 2018
24. Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs
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Hamideh Parhiz, Vladimir R. Muzykantov, Ambika Natesan, Dorottya Laczkó, Norbert Pardi, Ying K. Tam, Amir Yadegari, Drew Weissman, Hiromi Muramatsu, Mohamad-Gabriel Alameh, Hamna Shahnawaz, Vladimir V. Shuvaev, Tyler E. Papp, István Tombácz, and Barbara L. Mui
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CD4-Positive T-Lymphocytes ,COVID-19 Vaccines ,medicine.medical_treatment ,T cell ,Spleen ,Biology ,Transfection ,Mice ,Immune system ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Pharmacology ,Recombination, Genetic ,Messenger RNA ,Reporter gene ,Effector ,SARS-CoV-2 ,COVID-19 ,Immunotherapy ,Lipids ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Molecular Medicine ,Nanoparticles ,Lymph Nodes - Abstract
Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing ∼30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with non-targeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure.
- Published
- 2020
25. Non-cooperative game of participant choice in a public private partnership using a compromise solution
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Oleg Malafeyev, Askat Arzimbekov, Irina Zaitseva, Nadezhda Redinskikh, Elena Ostapenko, and A. V. Shuvaev
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Non-cooperative game ,Public–private partnership ,Property (philosophy) ,Relation (database) ,Operations research ,Optimality principle ,Computer science ,Compromise ,media_common.quotation_subject ,State (computer science) ,Numerical models ,media_common - Abstract
The non-cooperative game model of public private partnership is considered in this paper. Such partnerships is carried out through the implementation of social or infrastructure projects in relation to state and municipal property. In this paper the problem of identifying the best private partner is modeled as a static non-cooperative game with full information. A compromise solution is choosed as optimality principle. An algorithm of compromise solution is given in this paper. The numerical example is solved.
- Published
- 2020
26. Anti-inflammatory effect of targeted delivery of SOD to endothelium: mechanism, synergism with NO donors and protective effects in vitro and in vivo.
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Vladimir V Shuvaev, Jingyan Han, Samira Tliba, Evguenia Arguiri, Melpo Christofidou-Solomidou, Servio H Ramirez, Holly Dykstra, Yuri Persidsky, Dmitriy N Atochin, Paul L Huang, and Vladimir R Muzykantov
- Subjects
Medicine ,Science - Abstract
Pro-inflammatory activation of vascular endothelium is implicated in pathogenesis of severe conditions including stroke, infarction and sepsis. We have recently reported that superoxide dismutase (SOD) conjugated with antibodies (Ab/SOD) that provide targeted delivery into endothelial endosomes mitigates inflammatory endothelial activation by cytokines and agonists of Toll-like receptors (TLR). The goal of this study was to appraise potential utility and define the mechanism of this effect. Ab/SOD, but not non-targeted SOD injected in mice alleviated endotoxin-induced leukocyte adhesion in the cerebral vasculature and protected brain from ischemia-reperfusion injury. Transfection of endothelial cells with SOD, but not catalase inhibited NFκB signaling and expression of Vascular Cell Adhesion Molecule-1 induced by both cytokines and TLR agonists. These results affirmed that Ab/SOD-quenched superoxide anion produced by endothelial cells in response to proinflammatory agents mediates NFκB activation. Furthermore, Ab/SOD potentiates anti-inflammatory effect of NO donors in endothelial cells in vitro, as well as in the endotoxin-challenged mice. These results demonstrate the central role of intracellular superoxide as a mediator of pro-inflammatory activation of endothelium and support the notion of utility of targeted interception of this signaling pathway for management of acute vascular inflammation.
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- 2013
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27. Numerical Stability Analysis of Oil Collector Case Self-Excited Vibrations
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Kirill A. Vinogradov, Natalia O. Voronova, and Nikolay V. Shuvaev
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Vibration ,Materials science ,Self excited ,Mechanics ,Numerical stability - Abstract
The investigation subject is an Oil Collector Case which is a thin axisymmetric stator part with console binding to the turbine rear frame. It had been suffering from high level vibrations and needed fixing measures to apply. Self-excited vibrations supposed as the main reason for defects to occur. The problem was examined in the engine and test rig conditions. The energetic method which is usually applied to blade flutter problems was used for aeroelastic stability analysis. Radial surface displacements were set according to the harmonic oscillation function that corresponds to the oil collector’s first bending eigenmode with two nodal diameters. 3D aerodynamic model represents a 180° sector, thus ensures that surface displacements and gas parameters on periodic surfaces are equal. A set of simulations was carried out and calculated; the aerodynamic damping coefficient values showed aeroelastic instability predisposition in both the engine and test rig conditions for most test cases. Influence of such model parameters as seal radial clearance, pressure ratio, inlet air temperature, wave propagation direction and rotor speed was investigated. A detailed analysis showed that for instability case positive aerodynamic work region lies inside the oil collector cavern downstream labyrinth seal where pressure wave and surface displacement speed wave are close to synchrony. Probable excitation mechanisms were described and discussed. It was demonstrated that aeroelastic instability of the same type as it was in the engine conditions can be reproduced in the test rig conditions.
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- 2020
28. Bivalent engagement of endothelial surface antigens is critical to prolonged surface targeting and protein delivery in vivo
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R. Yu. Kiseleva, Vladimir V. Shuvaev, K. M. LeForte, Jacob W. Myerson, Oscar A. Marcos-Contreras, Carlos H. Villa, Pavel Aprelev, P. G. Glassman, Landis R. Walsh, Vladimir R. Muzykantov, and Colin F. Greineder
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0301 basic medicine ,Biodistribution ,Endothelium ,medicine.drug_class ,Pharmacology ,Thrombomodulin ,Monoclonal antibody ,Ligands ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Drug Delivery Systems ,Pharmacokinetics ,In vivo ,Genetics ,medicine ,Animals ,Humans ,Tissue Distribution ,Molecular Biology ,Lung ,ICAM-1 ,Chemistry ,Antibodies, Monoclonal ,Endothelial Cells ,Intercellular Adhesion Molecule-1 ,Platelet Endothelial Cell Adhesion Molecule-1 ,030104 developmental biology ,medicine.anatomical_structure ,Targeted drug delivery ,Endothelium, Vascular ,030217 neurology & neurosurgery ,Biotechnology ,Single-Chain Antibodies - Abstract
Targeted drug delivery to the endothelium has the potential to generate localized therapeutic effects at the blood-tissue interface. For some therapeutic cargoes, it is essential to maintain contact with the bloodstream to exert protective effects. The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy. To bridge this gap, we site-specifically radiolabeled mono- (scFv) and bivalent (mAb) affinity ligands specific for the endothelial cell adhesion molecules, PECAM-1 (CD31) and ICAM-1 (CD54). Radiotracing revealed similar lung biodistribution at 30 minutes post-injection (79.3% ± 4.2% vs 80.4% ± 10.6% ID/g for αICAM and 58.9% ± 3.6% ID/g vs. 47.7% ± 5.8% ID/g for αPECAM mAb vs. scFv), but marked differences in organ residence time, with antibodies demonstrating an order of magnitude greater area under the lung concentration vs. time curve (AUCinf 1698 ± 352 vs. 53.3 ± 7.9 ID/g*hrs for αICAM and 1023 ± 507 vs. 114 ± 37 ID/g*hrs for αPECAM mAb vs scFv). A physiologically based pharmacokinetic model, fit to and validated using these data, indicated contributions from both superior binding characteristics and prolonged circulation time supporting multiple binding-detachment cycles. We tested the ability of each affinity ligand to deliver a prototypical surface cargo, thrombomodulin (TM), using one-to-one protein conjugates. Bivalent mAb-TM was superior to monovalent scFv-TM in both pulmonary targeting and lung residence time (AUCinf 141 ± 3.2 vs 12.4 ± 4.2 ID/g*hrs for ICAM and 188 ± 90 vs 34.7 ± 19.9 ID/g*hrs for PECAM), despite having similar blood PK, indicating that binding strength is more important parameter than the kinetics of binding. To maximize bivalent target engagement, we synthesized an oriented, end-to-end anti-ICAM mAb-TM conjugate and found that this therapeutic had the best lung residence time (AUCinf 253 ± 18 ID/g*hrs) of all TM modalities. These observations have implications not only for the delivery of TM, but also potentially all therapeutics targeted to the endothelial surface.
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- 2020
29. Dual Targeted Red Blood Cell Hitchhiking: A Platform Liposomal Drug Delivery System to Improve Circulation Time and Increase Delivery to Target Organs
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Vladimir V. Shuvaev, J. S. Brenner, Vladimir R. Muzykantov, Elizabeth D. Hood, Laura T. Ferguson, and Tea Shuvaeva
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Red blood cell ,Liposome ,medicine.anatomical_structure ,business.industry ,Drug delivery ,Medicine ,Circulation time ,Pharmacology ,business ,Target organ - Published
- 2020
30. Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood-brain barrier
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Viviana Zuluaga-Ramirez, Thomas D. Madden, Makan Khoshnejad, Vladimir R. Muzykantov, Alecia Seliga, Landis R. Walsh, Ying K. Tam, Elizabeth D. Hood, Hamideh Parhiz, Patrick M. Glassman, Vladimir V. Shuvaev, Jacob S. Brenner, Yuri Persidsky, Raisa Yu Kiseleva, Carlos H. Villa, Norbert Pardi, Drew Weissmann, István Tombácz, Barbara L. Mui, Colin F. Greineder, Jacob W. Myerson, Oscar A. Marcos-Contreras, and Jia Nong
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Traumatic brain injury ,Thrombomodulin ,Intercellular Adhesion Molecule-1 ,Vascular Cell Adhesion Molecule-1 ,Blood–brain barrier ,Antibodies ,chemistry.chemical_compound ,Cerebral circulation ,Mice ,Receptors, Transferrin ,medicine ,Animals ,Humans ,VCAM-1 ,Multidisciplinary ,business.industry ,Cell adhesion molecule ,Tumor Necrosis Factor-alpha ,medicine.disease ,medicine.anatomical_structure ,Nanomedicine ,chemistry ,Blood-Brain Barrier ,Physical Sciences ,Cancer research ,Encephalitis ,Endothelium, Vascular ,Nanocarriers ,business ,Intravital microscopy - Abstract
Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood-brain barrier, thus benefiting numerous brain pathologies.
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- 2020
31. Targeting drug delivery in the vascular system: Focus on endothelium
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Vladimir V. Shuvaev, Raisa Yu Kiseleva, Laura T. Ferguson, Jacob W. Myerson, Patrick M. Glassman, Vladimir R. Muzykantov, and Jacob S. Brenner
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2019-20 coronavirus outbreak ,Endothelium ,Pharmaceutical Science ,Inflammation ,02 engineering and technology ,Article ,03 medical and health sciences ,Drug Delivery Systems ,medicine ,Animals ,Humans ,Degree of precision ,Vascular Diseases ,030304 developmental biology ,0303 health sciences ,business.industry ,Vascular inflammation ,Endothelial Cells ,021001 nanoscience & nanotechnology ,Nanomedicine ,medicine.anatomical_structure ,Vascular system ,Drug delivery ,Nanoparticles ,Endothelium, Vascular ,medicine.symptom ,Nanocarriers ,0210 nano-technology ,business ,Site of action ,Neuroscience - Abstract
The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges., Graphical abstract Unlabelled Image
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- 2020
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32. Co metal nanoparticles deposition inside or outside multi-walled carbon nanotubes via facile support pretreatment
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Andrey S. Andreev, Mariya A. Kazakova, Arcady V. Ishchenko, Alexander V. Shuvaev, Jean-Baptiste d'Espinose de Lacaillerie, Olga B. Lapina, Vladimir L. Kuznetsov, Alexander G. Selyutin, Novosibirsk State University (NSU), Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences (SB RAS), Sciences et Ingénierie de la Matière Molle (UMR 7615) (SIMM), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Siberian Transport University, and Genome Institute of Singapore (GIS)
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Materials science ,General Physics and Astronomy ,Nanoparticle ,02 engineering and technology ,Surfaces and Interfaces ,General Chemistry ,Carbon nanotube ,Penetration (firestop) ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,0104 chemical sciences ,Surfaces, Coatings and Films ,law.invention ,Ferromagnetism ,Chemical engineering ,law ,Transmission electron microscopy ,0210 nano-technology ,High-resolution transmission electron microscopy ,Porosity ,[PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft] ,ComputingMilieux_MISCELLANEOUS ,Powder diffraction - Abstract
Decoration of one-dimensional multi-walled carbon nanotubes (MWCNTs) with zero-dimensional Co nanoparticles leads to hybrid structures with chemical and electromagnetic features that are not available to the individual components. This work addresses the influence of the nature and structure of MWCNTs on the localization of Co nanoparticles. Depending on synthesis conditions, Co can be deposited on the external or in inner surfaces of the nanotubes. Co/MWCNTs hybrids have been characterized by in situ X-ray powder diffraction, high-resolution transmission electron microscopy and 59Co internal field nuclear magnetic resonance. It has been shown that the average diameter (7.2, 9.4 and 18.6 nm), number of walls (5–7, 12–15, 15–20), and functional composition of the MWCNTs have a remarkable effect on the size of Co nanoparticles and their distribution in the structure of MWCNTs. The observed phenomenon has been rationalized in terms of nanotubes surface properties. Parent MWCNTs being hydrophobic and having limited porosity do not stabilize Co nanoparticles and, therefore, they are localized on the outside surface with relatively large average size and broad size distribution. On the other hand, the oxidation of the MWCNTs resulted in the penetration of Co nanoparticles inside of the nanotubes, presumably because of pore opening as well as increased hydrophilicity of the nanotubes.
- Published
- 2018
33. Ferritin-based drug delivery systems: Hybrid nanocarriers for vascular immunotargeting
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Hamideh Parhiz, Vladimir R. Muzykantov, Vladimir V. Shuvaev, Ivan J. Dmochowski, and Makan Khoshnejad
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Models, Molecular ,Pharmaceutical Science ,Antineoplastic Agents ,Nanotechnology ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Article ,Drug Delivery Systems ,Nanocages ,Neoplasms ,Animals ,Humans ,Lung ,Drug Carriers ,Vaccines ,biology ,Extramural ,Chemistry ,021001 nanoscience & nanotechnology ,Uniform size ,0104 chemical sciences ,Ferritin ,Positron-Emission Tomography ,Ferritins ,Drug delivery ,biology.protein ,Blood Vessels ,Nanoparticles ,Nanocarriers ,0210 nano-technology - Abstract
Ferritin subunits of heavy and light polypeptide chains self-assemble into a spherical nanocage that serves as a natural transport vehicle for metals but can include diverse cargoes. Ferritin nanoparticles are characterized by remarkable stability, small and uniform size. Chemical modifications and molecular re-engineering of ferritin yield a versatile platform of nanocarriers capable of delivering a broad range of therapeutic and imaging agents. Targeting moieties conjugated to the ferritin external surface provide multivalent anchoring of biological targets. Here, we highlight some of the current work on ferritin as well as examine potential strategies that could be used to functionalize ferritin via chemical and genetic means to enable its utility in vascular drug delivery.
- Published
- 2018
34. Targeting superoxide dismutase to endothelial caveolae profoundly alleviates inflammation caused by endotoxin
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Melpo Christofidou-Solomidou, Evguenia Arguiri, Vladimir R. Muzykantov, Vladimir V. Shuvaev, Raisa Yu Kiseleva, Radu V. Stan, Carlos H. Villa, and Silvia Muro
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Lipopolysaccharides ,Male ,0301 basic medicine ,Endosome ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Inflammation ,Caveolae ,Endocytosis ,Antibodies ,Article ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Superoxide Dismutase ,Superoxide ,Membrane Proteins ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,TLR4 ,biology.protein ,Cytokines ,medicine.symptom ,Carrier Proteins - Abstract
Inflammatory mediators binding to Toll-Like receptors (TLR) induce an influx of superoxide anion in the ensuing endosomes. In endothelial cells, endosomal surplus of superoxide causes pro-inflammatory activation and TLR4 agonists act preferentially via caveolae-derived endosomes. To test the hypothesis that SOD delivery to caveolae may specifically inhibit this pathological pathway, we conjugated SOD with antibodies (Ab/SOD, size ~ 10 nm) to plasmalemmal vesicle-associated protein (Plvap) that is specifically localized to endothelial caveolae in vivo and compared its effects to non-caveolar target CD31/PECAM-1. Plvap Ab/SOD bound to endothelial cells in culture with much lower efficacy than CD31 Ab/SOD, yet blocked the effects of LPS signaling with higher efficiency than CD31 Ab/SOD. Disruption of cholesterol-rich membrane domains by filipin inhibits Plvap Ab/SOD endocytosis and LPS signaling, implicating the caveolae-dependent pathway(s) in both processes. Both Ab/SOD conjugates targeted to Plvap and CD31 accumulated in the lungs after IV injection in mice, but the former more profoundly inhibited LPS-induced pulmonary inflammation and elevation of plasma level of interferon-beta and -gamma and interleukin-27. Taken together, these results indicate that targeted delivery of SOD to specific cellular compartments may offer effective, mechanistically precise interception of pro-inflammatory signaling mediated by reactive oxygen species.
- Published
- 2018
35. The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series)
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Vladimir V. Shuvaev, Colin F. Greineder, Raisa Yu Kiseleva, Hamideh Parhiz, Vladimir R. Muzykantov, Patrick M. Glassman, Jacob S. Brenner, and Elizabeth D. Hood
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,lcsh:Diseases of the circulatory (Cardiovascular) system ,ARDS ,endothelium ,Endothelium ,Primary Graft Dysfunction ,Review Article ,Bioinformatics ,vascular targeting ,03 medical and health sciences ,Medicine ,lcsh:RC705-779 ,Lung ,business.industry ,lcsh:Diseases of the respiratory system ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Targeted drug delivery ,lcsh:RC666-701 ,inflammation ,drug delivery ,Drug delivery ,acute respiratory distress syndromes and acute lung injury ,Pulmonary vasculature ,business ,Drug carrier - Abstract
The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk–benefit ratio and safety—parameters one should keep in mind when developing a translational therapeutic.
- Published
- 2018
36. 1590P Treatment outcomes and antibody immunity to SARS-CoV-2 in patients with hematological malignancies
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K. Zakurdaeva, K. Kaplanov, V. G. Savchenko, S.K. Dubov, M.E. Grishunina, O. A. Gavrilina, A.A. Petrenko, L.S. Butaev, V.I. Vorobyev, M. Popova, A. Siniaev, L.V. Gavrilova, O.I. Ochirova, Y.V. Sveshnikova, A. N. Vasileva, V. Shuvaev, V.S. Dubov, E.Y. Chelysheva, Y. Chabaeva, and I.Y. Toropova
- Subjects
CD20 ,medicine.medical_specialty ,education.field_of_study ,Hematology ,biology ,business.industry ,Population ,medicine.disease ,Gastroenterology ,Article ,Lymphoma ,Vaccination ,Clinical trial ,Oncology ,Internal medicine ,biology.protein ,medicine ,Clinical endpoint ,education ,business ,Multiple myeloma - Abstract
Background: Since SARS-CoV-2 infection heavily affects vulnerable populations including those with immune suppression, it is of special value to study clinical course, treatment outcomes, and immunity in patients (pts) with hematological (hem) malignancies. Methods: CHRONOS19 is an ongoing observational study in adult pts (≥18 years) with hem diseases (malignant or non-malignant) and COVID-19 in Russia. This web-based registry collected de-identified data from 15 centers all over the country at 30, 90, and 180 days after lab-confirmed or suspected (based on CT and/or clinical symptoms) COVID-19 diagnosis. The primary endpoint was 30-day all-cause mortality. Results: As of data cut-off on April 14, 2021, 626 pts were enrolled in the study;562 were eligible for primary endpoint assessment, n (%): M/F 271 (48%) / 291 (52%), median age 56 [18-90] years, malignant disease in 516 (92%) pts, among them induction phase / relapse or refractory / remission / NA in 180 (35%) / 120 (23%) / 187 (36%) / 29 (6%) pts. Thirty-day all-cause mortality in pts with hem malignancies was 19%;83% of deaths were due to COVID-19 complications. No increase of hem disease relapse rate after COVID-19 was observed at Day 90 or Day 180, although 180-day data was still not mature at the time of analysis. IgG to SARS-CoV-2 was detected in 84% of pts with hem malignancies (167/199). The highest rate of detected antibody immunity was found in pts with chronic myeloproliferative neoplasms (100%;13/13), HL (100%;12/12), and multiple myeloma (97%;34/35), the lowest – in pts with CLL (62%;8/13) and NHL (60%;6/10 and 56%;10/18 for low-grade and high-grade lymphoma, respectively). igG detection rate in CD20+ lymphoma (60%) was significantly lower than in HL or T-cell lymphoma (p=0.004). Pts with ECOG 0-2 throughout the disease had a high rate of antibody immunity (90%;104/116) vs. those with ECOG 3-4 at the time of COVID-19 diagnosis (77.5%;31/40) or with worsening of ECOG to 3-4 during the disease (78%;36/46). Five cases of SARS-CoV-2 re-infection were described. Conclusions: Pts with hem malignancies and COVID-19 have higher mortality than the general population. Low post-disease antibody immunity to SARS-CoV-2 and cases of re-infection may justify vaccination of these pts and warrant further research. Clinical trial identification: NCT04422470. Legal entity responsible for the study: National Research Center for Hematology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
- Published
- 2021
37. A sensitive and simple targeted proteomics approach to quantify transcription factor and membrane proteins of the unfolded protein response pathway in glioblastoma cells
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Christin Lorenz, Stefan Reich, Stefan Loroch, Christiane B. Knobbe-Thomsen, Björn Tews, Sebastian Malchow, Konstantin V. Shuvaev, Chi D. L. Nguyen, Robert Ahrends, Albert Sickmann, Sascha Steltgens, and Jan Medenbach
- Subjects
Proteomics ,0301 basic medicine ,Cell ,Gene Dosage ,lcsh:Medicine ,Computational biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell surface receptor ,Transcription (biology) ,Cell Line, Tumor ,medicine ,Humans ,lcsh:Science ,Transcription factor ,Multidisciplinary ,Chemistry ,Effector ,lcsh:R ,Membrane Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Membrane protein ,Isotope Labeling ,Unfolded Protein Response ,Unfolded protein response ,lcsh:Q ,Signal transduction ,Glioblastoma ,Peptides ,030217 neurology & neurosurgery ,Cell signalling ,Transcription Factors - Abstract
Many cellular events are driven by changes in protein expression, measurable by mass spectrometry or antibody-based assays. However, using conventional technology, the analysis of transcription factor or membrane receptor expression is often limited by an insufficient sensitivity and specificity. To overcome this limitation, we have developed a high-resolution targeted proteomics strategy, which allows quantification down to the lower attomol range in a straightforward way without any prior enrichment or fractionation approaches. The method applies isotope-labeled peptide standards for quantification of the protein of interest. As proof of principle, we applied the improved workflow to proteins of the unfolded protein response (UPR), a signaling pathway of great clinical importance, and could for the first time detect and quantify all major UPR receptors, transducers and effectors that are not readily detectable via antibody-based-, SRM- or conventional PRM assays. As transcription and translation is central to the regulation of UPR, quantification and determination of protein copy numbers in the cell is important for our understanding of the signaling process as well as how pharmacologic modulation of these pathways impacts on the signaling. These questions can be answered using our newly established workflow as exemplified in an experiment using UPR perturbation in a glioblastoma cell lines.
- Published
- 2019
38. Boosting hydrodesulfurization activity of CoMo/Al2O3 catalyst via selective graphitization of alumina surface
- Author
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Igor P. Prosvirin, Oleg V. Klimov, Mariya A. Kazakova, Maxim O. Kazakov, Evgeniy Yu. Gerasimov, Alexander V. Shuvaev, A. S. Noskov, and Yulia V. Vatutina
- Subjects
chemistry.chemical_classification ,Materials science ,Sulfide ,chemistry.chemical_element ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,01 natural sciences ,0104 chemical sciences ,Catalysis ,chemistry.chemical_compound ,chemistry ,Chemical engineering ,Physisorption ,X-ray photoelectron spectroscopy ,Mechanics of Materials ,Dibenzothiophene ,Hydrodenitrogenation ,General Materials Science ,0210 nano-technology ,Cobalt ,Hydrodesulfurization - Abstract
The positive effect of alumina surface graphitization by CVD with ethylene on the activity of CoMo catalysts in hydrodesulfurization has been demonstrated. X-ray diffraction, Raman spectroscopy, High-resolution transmission electron microscopy, X-ray photoelectron spectroscopy and nitrogen physisorption showed that alumina surface graphitization does not significantly change the morphology and textural characteristics of the support. However, it has a significant impact on the morphology of supported sulfide component resulting in the formation of particles with a shorter slab length (2.9 vs 3.3 nm) and higher stacking number (2.4 vs 2.1) as compared to the sample based on γ-Al2O3. The results of CoMoS/γ-Al2O3 and CoMoS/C@γ-Al2O3 catalysts testing in hydrotreating reactions demonstrated a similar activity in hydrodenitrogenation of quinoline and 1.7 times higher activity of CoMoS/C@γ-Al2O3 in hydrodesulfurization of dibenzothiophene. Higher hydrodesulfurization activity of CoMoS/C@γ-Al2O3 sample is attributed to improved dispersion of the supported sulfide component and enhanced promotion of MoS2 by cobalt. Thus, the simple CVD approach presented here allows selective modification of the surface of commercially available alumina supports with a layer of graphite-like carbon and can be used to improve the activity of conventional hydrotreating catalysts.
- Published
- 2021
39. Using the Maple computer algebra system to study mathematical induction
- Author
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E. S. Kulevskaya, M. V. Migacheva, A. A. Olenev, A. V. Nazarenko, and A. V. Shuvaev
- Subjects
Algebra ,Maple ,History ,Computer science ,Mathematical induction ,engineering ,engineering.material ,Symbolic computation ,Computer Science Applications ,Education - Abstract
Mathematical induction is one of the main methods of the proof that students study and use it in their studies in higher education. This important method, in addition to mathematics, is widely used in computer science and a number of other related disciplines. However, even if the principles of proof using the method of induction are taught, understood and mastered by students well, many students have great difficulty with algebraic transformations necessary for proving, for example, finding the inductive step. The use of the Maple computer algebra system allows students to overcome this obstacle and, more attention and effort to pay to understanding the concept of proofs using the method of mathematical induction. In addition, students can prove more complex algebraic statements, and their activities can be of a pronounced research nature.
- Published
- 2020
40. Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates
- Author
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Vladimir V. Shuvaev, Melpo Christofidou-Solomidou, Vladimir R. Muzykantov, Silvia Muro, Samira Tliba, Evguenia Arguiri, and Makan Khoshnejad
- Subjects
0301 basic medicine ,Immunoconjugates ,Endosome ,Endocytic cycle ,Pharmaceutical Science ,Endosomes ,02 engineering and technology ,Endocytosis ,Article ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,Superoxides ,Human Umbilical Vein Endothelial Cells ,Extracellular ,Animals ,biology ,Superoxide Dismutase ,Cell adhesion molecule ,Superoxide ,Antibodies, Monoclonal ,Intercellular Adhesion Molecule-1 ,021001 nanoscience & nanotechnology ,Endotoxemia ,Cell biology ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,Oxidative Stress ,030104 developmental biology ,Biochemistry ,chemistry ,biology.protein ,Nanoparticles ,Endothelium, Vascular ,0210 nano-technology ,Intracellular - Abstract
Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300 nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively.
- Published
- 2016
41. The Role of Carrier Geometry in Overcoming Biological Barriers to Drug Delivery
- Author
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Vladimir V. Shuvaev, Carolyn T. Jordan, Vladimir R. Muzykantov, Thomas D. Dziubla, and Mark Bailey
- Subjects
Pharmacology ,Drug Carriers ,Extramural ,Chemistry, Pharmaceutical ,Biological Transport ,Nanotechnology ,Geometry ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Drug Delivery Systems ,Blood-Brain Barrier ,Drug Discovery ,Drug delivery ,Micron scale ,Animals ,Humans ,Nanoparticles ,0210 nano-technology ,Drug carrier ,Drug transport - Abstract
For a variety of diseases, effective therapy is severely limited or rendered impossible due to an inability to deliver medications to the intended sites of action. Multiple barriers exist through the body, which have evolved over time to limit the migration of foreign compounds from entering the tissues. Turning toward biology as inspiration, it has been the general goal of drug delivery to create carrier strategies that mimic, in part, features of bacteria/ viruses that allow them overcome these barriers. By packaging drugs into nano and micron scale vehicles, it should be possible to completely change the biodistribution and residence times of pharmaceutically active compounds. Recently, due to advances in formulation technologies, it has become possible to control not just the material selection, surface chemistry, and/or size, but also the overall geometry and plasticity of the drug carriers. These approaches aid in the formulation of nonspherical particles such as, discs, rods, and even unique structures such as cubes and nanodiamonds. The adjustment of size and shape can be used for the aid or prevention in cellular uptake and also to overcome the vascular and mucosal barrier. In this review, we present a summary of some approaches used to control carrier shape and the impact these geometries have upon drug transport across biological barriers.
- Published
- 2016
42. О подпоследовательностях марковских последовательностей
- Author
-
D V Shuvaev
- Published
- 2016
43. Simulation of multi-agent interaction between mobile operators and users
- Author
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I. F. Kefeli, O. A. Malafeyev, Irina Zaitseva, A. V. Shuvaev, and Natalya Poddubnaya
- Subjects
Computer science ,Distributed computing - Abstract
Game-theoretic models for two classes of players are considered in this paper. The first class will consist of mobile operators, who, based on information about competitors’ actions, will plan changes in prices for services. The second class will consist of dedicated user cohorts who, depending on the current situation, will plan their actions, namely, change or not change the operator. The presented models solve the problem of maximizing the income of mobile operators and minimizing the cost of communication by users. A turn-based game is considered where a possible strategy for a first-class player will be considered a non-zero price vector for the provided communication services. A possible strategy for a second-class player will be considered the sequence of choosing a mobile operator for each of the services. The payoff function of both classes players will be built at each stage. According to the winnings, there is a compromise solution for different classes of players.
- Published
- 2020
44. Restructuring of Tax Liabilities as an Upcoming Trend of Economic Diversification in Modern Russia
- Author
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Anastasia A. Sozinova, Natalya A. Shibaeva, Alexander N. Alekseev, Anna I. Zarudneva, and A. V. Shuvaev
- Subjects
Restructuring ,media_common.quotation_subject ,05 social sciences ,0507 social and economic geography ,Legislature ,Diversification (marketing strategy) ,050701 cultural studies ,0506 political science ,Trend analysis ,Market economy ,Consolidation (business) ,Order (exchange) ,Bankruptcy ,Service (economics) ,050602 political science & public administration ,Business ,media_common - Abstract
Purpose The purpose of the paper is to substantiate possible and necessary use of restructuring of tax liabilities as an upcoming trend of economic diversification in modern Russia, and to develop practical recommendations. Methodology In this paper we apply a complex of general scientific methods, as well as methods of time-series analysis in economic statistics—horizontal and trend analysis. Information and empirical background is provided by data of the Center for Macroeconomic Analysis and Short-Term Forecasting of the Russian Federation, RIA Rating, and Federal State Statistics Service of the Russian Federation (Rosstat). To define the relevance of the mechanism for restructuring tax liabilities in modern Russia, the authors address to dynamic pattern of enterprises and closed down ones due to bankruptcy in 2007–2017. Results As a result, we had proved that the restructuring of tax liabilities is an upcoming trend of economic diversification in modern Russia. It is revealed that over recent years, the demand for this mechanism in relation to growing unprofitability of enterprises and their frequent close-down due to bankruptcy has increased in Russian economic system. However, the state introduces tight restrictions for enterprises restructuring their tax liabilities to protect own interests (guaranteed replenishment of budget and extra-budgetary funds). Recommendations In order to ensure widespread availability of the mechanism to restructure tax liabilities for modern Russian enterprises, it is advised legislative consolidation of priority implementation of restructured tax liabilities. To aim this mechanism at diversification of the Russian economy, we propose to grant preferential terms (reduced limit of tax liabilities and extended term of their restructuring) for enterprises of the most promising and strategically crucial branches of national economy in terms of economic diversification.
- Published
- 2018
45. PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake
- Author
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Thomas G. Uhler, Steven Tuyishime, Vladimir V. Shuvaev, Norbert Pardi, Ying K. Tam, Hamideh Parhiz, Michael J. Hope, Barbara L. Mui, Vladimir R. Muzykantov, Jacob S. Brenner, Drew Weissman, Raisa Yu Kiseleva, Thomas D. Madden, and Makan Khoshnejad
- Subjects
0301 basic medicine ,Apolipoprotein E ,Immunoconjugates ,Apolipoprotein B ,Pharmaceutical Science ,Inflammation ,Pharmacology ,Protein expression ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Drug Delivery Systems ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Tissue Distribution ,RNA, Messenger ,Messenger RNA ,Drug Carriers ,biology ,Chemistry ,Cell adhesion molecule ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Systemic administration ,Nanoparticles ,Administration, Intravenous ,Endothelium, Vascular ,medicine.symptom ,Antibody - Abstract
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
- Published
- 2018
46. Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles
- Author
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Colin F. Greineder, Hyun-Su Lee, Russell J. Composto, Patrick M. Glassman, Radu V. Stan, Martha E. Grady, Bruce Braender, Vladimir R. Muzykantov, Olivia M. McPherson, Raisa Yu Kiseleva, Vladimir V. Shuvaev, Jacob W. Myerson, Oscar A. Marcos-Contreras, and David M. Eckmann
- Subjects
Materials science ,Nanoparticle ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Article ,Polyethylene Glycols ,chemistry.chemical_compound ,Mice ,Drug Delivery Systems ,Caveolae ,Animals ,Polyethyleneimine ,General Materials Science ,Drug Carriers ,Mechanical Engineering ,Quartz crystal microbalance ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Membrane ,chemistry ,Mechanics of Materials ,Biophysics ,Nanomedicine ,Nanoparticles ,Polystyrene ,Nanocarriers ,0210 nano-technology ,Drug carrier - Abstract
Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites of disease or injury with minimized systemic effects. Precise targeting demands addressing to subcellular features, among which caveolae, invaginations in the cell membrane implicated in transcytosis and inflammatory signaling, are appealing targets. Caveolar geometry was reported to impose a ~50nm size cutoff on nanocarrier access to plasmalemma vesicle associated protein (PLVAP), a marker found in caveolae in the lungs. We explored the use of deformable nanocarriers to overcome that size cutoff. Lysozyme-dextran nanogels (NGs) were synthesized with ~150nm or ~300nm mean diameter. AFM indicated deformability of NGs on complementary surfaces. Quartz crystal microbalance data indicated that NGs formed softer monolayers (~60kPa) than polystyrene particles (~8MPa). NGs deformed during flow through microfluidic channels, and modeling of NG extrusion through porous filters yielded sieving diameters of less than 25nm for NGs with 150nm and 300nm hydrodynamic diameters. In mouse lungs, where PLVAP is primarily localized to caveolae, NGs of 150nm and 300nm diameter targeted PLVAP while rigid polystyrene particles did not. Our data indicate a role for mechanical deformability in targeting large high-payload drug delivery vehicles to sterically obscured targets like PLVAP.
- Published
- 2018
47. Vascular endothelial effects of collaborative binding to platelet/endothelial cell adhesion molecule-1 (PECAM-1)
- Author
-
Carlos H. Villa, Vladimir V. Shuvaev, Horace M. DeLisser, Elizabeth D. Hood, Colin F. Greineder, Raisa Yu Kiseleva, Vladimir R. Muzykantov, and Oscar A. Marcos-Contreras
- Subjects
0301 basic medicine ,medicine.medical_treatment ,lcsh:Medicine ,Plasma protein binding ,Cell junction ,Epitope ,Article ,Antibodies ,Permeability ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,In vivo ,Antigens, CD ,medicine ,Animals ,Humans ,lcsh:Science ,Cells, Cultured ,Multidisciplinary ,Chemistry ,lcsh:R ,Endothelial Cells ,Cadherins ,In vitro ,Cell biology ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Drug delivery ,Cytokines ,lcsh:Q ,Protein Binding - Abstract
Targeting drugs to endothelial cells has shown the ability to improve outcomes in animal models of inflammatory, ischemic and thrombotic diseases. Previous studies have revealed that certain pairs of ligands (antibodies and antibody fragments) specific for adjacent, but distinct, epitopes on PECAM-1 enhance each other’s binding, a phenomenon dubbed Collaborative Enhancement of Paired Affinity Ligands, or CEPAL. This discovery has been leveraged to enable simultaneous delivery of multiple therapeutics to the vascular endothelium. Given the known role of PECAM-1 in promoting endothelial quiescence and cell junction integrity, we sought here to determine if CEPAL might induce unintended vascular effects. Using a combination of in vitro and in vivo techniques and employing human and mouse endothelial cells under physiologic and pathologic conditions, we found only modest or non-significant effects in response to antibodies to PECAM-1, whether given solo or in pairs. In contrast, these methods detected significant elevation of endothelial permeability, pro-inflammatory vascular activation, and systemic cytokine release following antibody binding to the related endothelial junction protein, VE-Cadherin. These studies support the notion that PECAM-1-targeted CEPAL provides relatively well-tolerated endothelial drug delivery. Additionally, the analysis herein creates a template to evaluate potential toxicities of vascular-targeted nanoparticles and protein therapeutics.
- Published
- 2018
48. Innovational Tools for Provision of Food Security Through State Support for the Agro-Industrial Complex in the Conditions of Digital Economy
- Author
-
Alexander V. Shuvaev, Pavel M. Taranov, and Aleksei V. Bogoviz
- Subjects
Entrepreneurship ,Food security ,media_common.quotation_subject ,0211 other engineering and technologies ,Subsidy ,02 engineering and technology ,Competitive advantage ,Competition (economics) ,020303 mechanical engineering & transports ,0203 mechanical engineering ,Market mechanism ,021105 building & construction ,Quality (business) ,Business ,Digital economy ,Industrial organization ,media_common - Abstract
The purpose of the article is to develop the innovational tools of provision of food security through state support for the agro-industrial complex (AIC) in the conditions of digital economy in modern Russia. For verification of the offered hypothesis and determination of connection between the level of national food security of modern Russia, state support for the AIC, and the use of the possibilities of digital economy, the article uses the method of correlation analysis. Also, the authors use the method of trend and horizontal statistical analysis, with the help of which the authors use the dynamics of change of the index of national food security in Russia in 2012–2017. The authors substantiate that state support for the AIC in modern Russia is not related to usage of existing possibilities of digital economy and does not fully ensure the national food security. The authors offer to supplement the traditional tools of financial support for national manufacturers of the AIC products with state subsidies, subsidized credits, etc., as well as innovational tools which is based on usage of the capabilities of digital economy. These tools allow achieving competitive advantages of domestic manufacturers of the AIC as to the quality and price. As compared to the traditional tools of state support, which belongs to the sphere of protectionism, the offered innovational tools do not limit the foreign competition and does not provide obvious preferences for domestic entrepreneurship. Instead, innovational tools increase competitiveness of domestic manufacturers of the AIC products, i.e., uses the market mechanism, leaving the choice to customers, hindering access to the market for dishonest entrepreneurs.
- Published
- 2018
49. PB2369 THE METHOD OF STORAGE OF AUTOLOGOUS PERIPHERAL BLOOD HEMATOPOIETIC STEM CELLS
- Author
-
M. Mikhaleva, A. Garifullin, A. Kuzyaeva, V. Shuvaev, A. Schmidt, S. Linnikov, G. Rysev, A. Kuvshinov, and S. Voloshin
- Subjects
Pathology ,medicine.medical_specialty ,Haematopoiesis ,business.industry ,medicine ,Hematology ,Stem cell ,business ,Peripheral blood - Published
- 2019
50. PB2232 THE NATURAL ANTICOAGULANTS IN PATIENTS WITH PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS
- Author
-
N. Korsakova, M. Fominykh, E. Efremova, O. Matvienko, S. Voloshin, L. Polushkina, N. Silina, L. Papayan, V. Shuvaev, O. Golovina, I. Martynkevich, and A. Samorodova
- Subjects
Philadelphia negative ,medicine.medical_specialty ,business.industry ,Medicine ,In patient ,Hematology ,business ,Dermatology - Published
- 2019
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