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Dive into the research topics where Vladimir R. Muzykantov is active.

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Featured researches published by Vladimir R. Muzykantov.


Science | 2012

Multifunctional Nanoparticles: Cost Versus Benefit of Adding Targeting and Imaging Capabilities

Zhiliang Cheng; Ajlan Al Zaki; James Z. Hui; Vladimir R. Muzykantov; Andrew Tsourkas

Nanoparticle-based drug delivery systems have been developed to improve the efficacy and reduce the systemic toxicity of a wide range of drugs. Although clinically approved nanoparticles have consistently shown value in reducing drug toxicity, their use has not always translated into improved clinical outcomes. This has led to the development of “multifunctional” nanoparticles, where additional capabilities like targeting and image contrast enhancement are added to the nanoparticles. However, additional functionality means additional synthetic steps and costs, more convoluted behavior and effects in vivo, and also greater regulatory hurdles. The trade-off between additional functionality and complexity is the subject of ongoing debate and the focus of this Review.


Molecular Therapy | 2008

Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers.

Silvia Muro; Carmen Garnacho; Julie A. Champion; John Leferovich; Christine Gajewski; Edward H. Schuchman; Samir Mitragotri; Vladimir R. Muzykantov

Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1-10 mum) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule-mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics.


Journal of Cell Science | 2003

A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1

Silvia Muro; Rainer Wiewrodt; Anu Thomas; Lauren Koniaris; Steven M. Albelda; Vladimir R. Muzykantov; Michael Koval

Antibody conjugates directed against intercellular adhesion molecule (ICAM-1) or platelet-endothelial cell adhesion molecule (PECAM-1) have formed the basis for drug delivery vehicles that are specifically recognized and internalized by endothelial cells. There is increasing evidence that ICAM-1 and PECAM-1 may also play a role in cell scavenger functions and pathogen entry. To define the mechanisms that regulate ICAM-1 and PECAM-1 internalization, we examined the uptake of anti-PECAM-1 and anti-ICAM-1 conjugates by endothelial cells. We found that the conjugates must be multimeric, because monomeric anti-ICAM-1 and anti-PECAM-1 are not internalized. Newly internalized anti-ICAM-1 and anti-PECAM-1 conjugates did not colocalize with either clathrin or caveolin, and immunoconjugate internalization was not reduced by inhibitors of clathrin-mediated or caveolar endocytosis, suggesting that this is a novel endocytic pathway. Amiloride and protein kinase C (PKC) inhibitors, agents known to inhibit macropinocytosis, reduced the internalization of clustered ICAM-1 and PECAM-1. However, expression of dominant-negative dynamin-2 constructs inhibited uptake of clustered ICAM-1. Binding of anti-ICAM-1 conjugates stimulated the formation of actin stress fibers by human umbilical vein endothelial cells (HUVEC). Latrunculin, radicicol and Y27632 also inhibited internalization of clustered ICAM-1, suggesting that actin rearrangements requiring Src kinase and Rho kinase (ROCK) were required for internalization. Interestingly, these kinases are part of the signal transduction pathways that are activated when circulating leukocytes engage endothelial cell adhesion molecules, suggesting the possibility that CAM-mediated endocytosis is regulated using comparable signaling pathways.


Proceedings of the National Academy of Sciences of the United States of America | 2002

1-Cys peroxiredoxin overexpression protects cells against phospholipid peroxidation-mediated membrane damage

Yefim Manevich; Tom Sweitzer; Jhang Ho Pak; Sheldon I. Feinstein; Vladimir R. Muzykantov; Aron B. Fisher

1-Cys peroxiredoxin (1-cysPrx) is a novel antioxidant enzyme able to reduce phospholipid hydroperoxides in vitro by using glutathione as a reductant. This enzyme is widely expressed and is enriched in lungs. A fusion protein of green fluorescent protein with 1-cysPrx was stably expressed in a lung-derived cell line (NCI-H441) lacking endogenous enzyme. Overexpressing cells (C17 or C48) degraded H2O2 and t-butylhydroperoxide more rapidly and showed decreased sensitivity to oxidant stress as measured by 51Cr release. On exposure to •OH generated by Cu2+-ascorbate (Asc), overexpressing cells compared with H441 showed less increase in thiobarbituric acid-reactive substance and phosphatidylcholine hydroperoxide content. This effect was reversed by depletion of cellular glutathione. Diphenyl-1-pyrenoylphosphonium fluorescence, used as a real-time probe of membrane phospholipid peroxidation, increased immediately on exposure to Cu2+-Asc and was abolished by preincubation of cells with Trolox (a soluble vitamin E) or Tempol (a radical scavenger). The rate of diphenyl-1-pyrenoylphosphonium fluorescence increase with Cu2+-Asc exposure was markedly attenuated in C17 and C48 cells as compared with H441. Annexin V-Cy3 was used to detect phosphatidylserine translocation from the inner to outer leaflet of the plasma membrane. Cu2+-Asc treatment induced phosphatidylserine translocation within 2 h in H441 cells but none was observed in C48 cells up to 24 h. These results indicate that 1-cysPrx can scavenge peroxides but in addition can reduce peroxidized membrane phospholipids. Thus, the enzyme can protect cells against oxidant-induced plasma membrane damage, thereby playing an important role in cellular defense against oxidant stress.


Expert Opinion on Drug Delivery | 2010

Drug delivery by red blood cells: vascular carriers designed by mother nature

Vladimir R. Muzykantov

Importance of the field: Vascular delivery of several classes of therapeutic agents may benefit from carriage by red blood cells (RBC), for example, drugs that require delivery into phagocytic cells and those that must act within the vascular lumen. The fact that several protocols of infusion of RBC-encapsulated drugs are now being explored in patients illustrates a high biomedical importance for the field. Areas covered by this review: Two strategies for RBC drug delivery are discussed: encapsulation into isolated RBC ex vivo followed by infusion in compatible recipients and coupling therapeutics to the surface of RBC. Studies of pharmacokinetics and effects in animal models and in human studies of diverse therapeutic enzymes, antibiotics and other drugs encapsulated in RBC are described and critically analyzed. Coupling to RBC surface of compounds regulating immune response and complement, affinity ligands, polyethylene glycol alleviating immune response to donor RBC and fibrinolytic plasminogen activators are described. Also described is a new, translation-prone approach for RBC drug delivery by injection of therapeutics conjugated with fragments of antibodies providing safe anchoring of cargoes to circulating RBC, without need for ex vivo modification and infusion of RBC. What the reader will gain: Readers will gain historical perspective, current status, challenges and perspectives of medical applications of RBC for drug delivery. Take home message: RBC represent naturally designed carriers for intravascular drug delivery, characterized by unique longevity in the bloodstream, biocompatibility and safe physiological mechanisms for metabolism. New approaches for encapsulating drugs into RBC and coupling to RBC surface provide promising avenues for safe and widely useful improvement of drug delivery in the vascular system.


Journal of Controlled Release | 2001

Targeting of superoxide dismutase and catalase to vascular endothelium

Vladimir R. Muzykantov

Reactive oxygen species, such as superoxide anion (O2(-)) and H2O2, cause oxidative stress in endothelial cells, a condition implicated in the pathogenesis of many cardiovascular and pulmonary diseases. Antioxidant enzymes, superoxide dismutases (SOD, converting superoxide anion into H2O2) and catalase (converting H2O2 into water), are candidate drugs for augmentation of antioxidant defenses in endothelium. However, SOD and catalase undergo fast elimination from the bloodstream, which compromises delivery and permits rather modest, if any, protection against vascular oxidative stress. Coupling of polyethylene glycol (PEG) to the enzymes and encapsulating them in liposomes increases their bioavailability and enhances their protective effect. Chemical modifications and genetic manipulations of SOD and catalase have been proposed in order to provide more effective delivery to endothelium. For example, chimeric protein constructs consisting of SOD and heparin-binding peptides have an affinity for charged components of the endothelial glycocalix. However, the problem of developing a more effective and precise delivery of the drugs to endothelial cells persists. Endothelial surface antigens may be employed to provide targeting and subcellular addressing of drugs (vascular immunotargeting strategy). Thus, SOD and catalase conjugated to antibodies directed against the constitutively expressed endothelial antigens, angiotensin-converting enzyme (ACE) and adhesion molecules (ICAM-1 or PECAM-1), bind to endothelium in intact animals after intravascular administration, accumulate in the pulmonary vasculature, enter endothelial cells and augment their antioxidant defenses. Such immunotargeting strategies may provide secondary therapeutic benefits by inhibiting the function of target antigens. For example, blocking of ICAM-1 and PECAM-1 by carrier antibodies may attenuate inflammation and leukocyte-mediated vascular damage. Additional studies in animal models of vascular oxidative stress are necessary in order to more fully characterize potential therapeutic effects and limitations of targeting of antioxidant enzymes to endothelial cells.


Journal of Biological Chemistry | 2004

Pro-thrombotic State Induced by Post-translational Modification of Fibrinogen by Reactive Nitrogen Species

Caryn Vadseth; José M. Souza; Leonor Thomson; Amy Seagraves; Chandrasekaran Nagaswami; Tomas Scheiner; Jim Torbet; Gaston Vilaire; Joel S. Bennett; Juan Carlos Murciano; Vladimir R. Muzykantov; Marc S. Penn; Stanley L. Hazen; John W. Weisel; Harry Ischiropoulos

Formation of nitric oxide-derived oxidants has been linked to development of atherosclerosis and associated thrombotic complications. Although systemic levels of protein nitrotyrosine predict risk for coronary artery disease, neither specific proteins targeted for modification nor functional consequences that might contribute to disease pathogenesis have been defined. Here we report a selective increase in circulating levels of nitrated fibrinogen in patients with coronary artery disease. Exposure of fibrinogen to nitrating oxidants, including those produced by the myeloperoxidase-hydrogen peroxide-nitrite system, significantly accelerates clot formation and factor XIII cross-linking, whereas exposure of fibrinogen to non-nitrating oxidants decelerates clot formation. Clots formed with fibrinogen exposed to nitrating oxidants are composed of large bundles made from twisted thin fibrin fibers with increased permeation and a decrease in storage modulus G′ value, suggesting that these clots could be easily deformed by mechanical stresses. In contrast, clots formed with fibrinogen exposed to non-nitrating oxidants showed decreased permeation with normal architecture. Fibrinogen modified by exposure to physiologic nitration systems demonstrated no difference in the rate of plasmin-induced clot lysis, platelet aggregation, or binding. Thus, increased levels of fibrinogen nitration may lead to a pro-thrombotic state via acceleration in formation of fibrin clots. The present results may account, in part, for the association between nitrative stress and risk for coronary artery disease.


Journal of Pharmacology and Experimental Therapeutics | 2006

Endothelial Targeting of High-Affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1

Silvia Muro; Thomas D. Dziubla; Weining Qiu; John Leferovich; Xiumin Cui; Erik Berk; Vladimir R. Muzykantov

Targeting of diagnostic and therapeutic agents to endothelial cells (ECs) provides an avenue to improve treatment of many maladies. For example, intercellular adhesion molecule 1 (ICAM-1), a constitutive endothelial cell adhesion molecule up-regulated in many diseases, is a good determinant for endothelial targeting of therapeutic enzymes and polymer nanocarriers (PNCs) conjugated with anti-ICAM (anti-ICAM/PNCs). However, intrinsic and extrinsic factors that control targeting of anti-ICAM/PNCs to ECs (e.g., anti-ICAM affinity and PNC valency and flow) have not been defined. In this study we tested in vitro and in vivo parameters of targeting to ECs of anti-ICAM/PNCs consisting of either prototype polystyrene or biodegradable poly(lactic-coglycolic) acid polymers (∼200 nm diameter spheres carrying ∼200 anti-ICAM molecules). Anti-ICAM/PNCs, but not control IgG/PNCs 1) rapidly (t1/2 ∼5 min) and specifically bound to tumor necrosis factor-activated ECs in a dose-dependent manner (Bmax ∼350 PNC/cell) at both static and physiological shear stress conditions and 2) bound to ECs and accumulated in the pulmonary vasculature after i.v. injection in mice. Anti-ICAM/PNCs displayed markedly higher EC affinity versus naked anti-ICAM (Kd ∼80 pM versus ∼8 nM) in cell culture and, probably because of this factor, higher value (185.3 ± 24.2 versus 50.5 ± 1.5% injected dose/g) and selectivity (lung/blood ratio 81.0 ± 10.9 versus 2.1 ± 0.02, in part due to faster blood clearance) of pulmonary targeting. These results 1) show that reformatting monomolecular anti-ICAM into high-affinity multivalent PNCs boosts their vascular immuno-targeting, which withstands physiological hydrodynamics and 2) support potential anti-ICAM/PNCs utility for medical applications.


Expert Opinion on Drug Delivery | 2008

Polymeric carriers: role of geometry in drug delivery

Eric Simone; Thomas D. Dziubla; Vladimir R. Muzykantov

The unique properties of synthetic nanostructures promise a diverse set of applications as carriers for drug delivery, which are advantageous in terms of biocompatibility, pharmacokinetics, targeting and controlled drug release. Historically, more traditional drug delivery systems have focused on spherical carriers. However, there is a growing interest in pursuing non-spherical carriers, such as elongated or filamentous morphologies, now available due to novel formulation strategies. Unique physiochemical properties of these supramolecular structures offer distinct advantages as drug delivery systems. In particular, results of recent studies in cell cultures and lab animals indicate that rational design of carriers of a given geometry (size and shape) offers an unprecedented control of their longevity in circulation and targeting to selected cellular and subcellular locations. This article reviews drug delivery aspects of non-spherical drug delivery systems, including material selection and formulation, drug loading and release, biocompatibility, circulation behavior, targeting and subcellular addressing.


Nature Biotechnology | 2003

Immunotargeting of catalase to the pulmonary endothelium alleviates oxidative stress and reduces acute lung transplantation injury

Benjamin D. Kozower; Melpo Christofidou-Solomidou; Thomas Sweitzer; Silvia Muro; Donald G. Buerk; Charalambos C. Solomides; Steven M. Albelda; G. Alexander Patterson; Vladimir R. Muzykantov

Vascular immunotargeting may facilitate the rapid and specific delivery of therapeutic agents to endothelial cells. We investigated whether targeting of an antioxidant enzyme, catalase, to the pulmonary endothelium alleviates oxidative stress in an in vivo model of lung transplantation. Intravenously injected enzymes, conjugated with an antibody to platelet-endothelial cell adhesion molecule-1, accumulate in the pulmonary vasculature and retain their activity during prolonged cold storage and transplantation. Immunotargeting of catalase to donor rats augments the antioxidant capacity of the pulmonary endothelium, reduces oxidative stress, ameliorates ischemia-reperfusion injury, prolongs the acceptable cold ischemia period of lung grafts, and improves the function of transplanted lung grafts. These findings validate the therapeutic potential of vascular immunotargeting as a drug delivery strategy to reduce endothelial injury. Potential applications of this strategy include improving the outcome of clinical lung transplantation and treating a wide variety of endothelial disorders.

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Steven M. Albelda

University of Pennsylvania

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Aron B. Fisher

University of Pennsylvania

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Elizabeth D. Hood

University of Pennsylvania

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Carlos H. Villa

University of Pennsylvania

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Sergei M. Danilov

University of Illinois at Chicago

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