In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors

Eniola, A. Omolola; Hammer, Daniel A.

doi:10.1016/j.biomaterials.2005.05.005

Cited by 75 publications

(40 citation statements)

References 41 publications

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“…Hence, comparison of static studies to experimental and theoretical models introducing flow dynamics is highly relevant. 7, 11, 13, 31, 53, 59, 60 Nevertheless, these results hold significance for tissues where flow is less apparent, and in vascular capillaries and postcapillary venules with almost-static conditions. 61 …”

Section: Resultsmentioning

confidence: 91%

How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers

et al. 2016

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Targeting of drug carriers to endocytic cell-receptors facilitates intracellular drug delivery. Carrier size and number of targeting moieties (valency) influence cell binding and uptake. However, how these parameters influence receptor-mediated cell-signaling (the link between binding and uptake) remains uncharacterized. We studied this using polymer carriers of different sizes and valencies, targeted to endothelial intercellular adhesion molecule-1 (ICAM-1), a marker overexpressed in many pathologies. Unexpectedly, induction of cell-signals (ceramide and PKC enrichment and activation) and uptake, were independent of: carrier avidity, total number of carriers bound per cell, cumulative cell-surface area occupied by carriers, number of targeting antibodies at the carrier-cell contact, and cumulative receptor engagement by all bound carriers. Instead, “valency density” (number of antibodies per carrier surface area) ruled signaling, and carrier size independently influenced uptake. These results are key to understanding the interplay between carrier design parameters and receptor-mediated signaling conducive to endocytosis, paramount for intracellular drug delivery.

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Section: Resultsmentioning

confidence: 91%

How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers

et al. 2016

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“…[14][15][16][17][18] Due to the ubiquitous presence of endothelium in the blood vessels of all calibers, the constant exposure of these cells to SS, and their sensitivity to interaction with other celladhesion molecules, vascular endothelium could be targeted for systemically administered NP-based therapies. 12,19 There are different classes of NP available for biomedical applications. Inorganic, biocompatible, porous ceramic NPs (eg, SiO 2 ) can be used for cancer therapy.…”

Section: O R I G I N a L R E S E A R C Hmentioning

confidence: 99%

“…11 In addition, poly-(lactic-co-glycolic acid) microspheres cofunctionalized with a selectin ligand and an antibody against ICAM-1 have been used for the leukocyte-mimetic targeting of endothelium. 12 Based on the importance of SS to EC function and integrity, it is likely that the mechanoreceptors activate intracellular signaling pathways to influence the complete endothelial response to SS. 13 Interestingly, in humans, the mean SS varies between 0.05 and 0.76 Pa in the veins, 0.3 and 0.7 Pa in the peripheral arteries (eg, the brachial artery, the femoral artery), and 1.0 and 1.5 Pa in the central arteries (eg, the carotid artery).…”

mentioning

confidence: 99%

Multifactorial determinants that govern nanoparticle uptake by human endothelial cells under flow

Samuel¹,

Jain²,

O'Dowd³

et al. 2012

IJN

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Vascular endothelium is a potential target for therapeutic intervention in diverse pathological processes, including inflammation, atherosclerosis, and thrombosis. By virtue of their intravascular topography, endothelial cells are exposed to dynamically changing mechanical forces that are generated by blood flow. In the present study, we investigated the interactions of negatively charged 2.7 nm and 4.7 nm CdTe quantum dots and 50 nm silica particles with cultured endothelial cells under regulated shear stress (SS) conditions. Cultured cells within the engineered microfluidic channels were exposed to nanoparticles under static condition or under low, medium, and high SS rates (0.05, 0.1, and 0.5 Pa, respectively). Vascular inflammation and associated endothelial damage were simulated by treatment with tumor necrosis factor-α (TNF-α) or by compromising the cell membrane with the use of low Triton X-100 concentration. Our results demonstrate that SS is critical for nanoparticle uptake by endothelial cells. Maximal uptake was registered at the SS rate of 0.05 Pa. By contrast, endothelial exposure to mild detergents or TNF-α treatment had no significant effect on nanoparticle uptake. Atomic force microscopy demonstrated the increased formation of actin-based cytoskeletal structures, including stress fibers and membrane ruffles, which have been associated with nanoparticle endocytosis. In conclusion, the combinatorial effects of SS rates, vascular endothelial conditions, and nanoparticle physical and chemical properties must be taken into account for the successful design of nanoparticle-drug conjugates intended for parenteral delivery. Keywords: endothelium, shear stress, quantum dots, membrane ruffling, stress fibers, atomic force microscopy, microfluidics Nanoparticle (NP) technologies are significantly affecting the development of both therapeutic and diagnostic agents. Although enormous progress in the field of nanotechnology has been achieved, basic discoveries have not yet translated into effective targeted therapies. NPs can potentially improve the pharmacokinetics and pharmacodynamics of drugs; however, the complexity of in vivo systems imposes multiple barriers that severely inhibit efficiency, which must be overcome to fully exploit the theoretical potential of NPs. Endothelial cells (ECs) that line the interior of the entire vascular system represent a major barrier for therapeutic agents traveling from the bloodstream to the target tissues. Recent studies have focused on targeting the endothelium with NPs as therapeutic agents for a variety of pathological conditions in the vascular system because of the large population of ECs and their proximity to the blood flow.ECs in vivo are exposed to a variety of hemodynamic forces that are created by blood flow and by the pulse wave dictated by the cardiac cycle. Shear stress (SS) is the dragging mechanical force that acts at the interface between flowing blood and Dovepress submit your manuscript | www.dovepress.com the vessel wall. ECs recognize SS a...

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“…Surprisingly, to our knowledge, no quantitative studies have sought to describe the effects of soluble adhesion IgSF proteins contained in human serum on the adhesion profile of these constructs in an in vivo or in vitro system. Prior studies have focused on the most commonly upregulated ligands, such as ICAM-1, VCAM-1, P-Selectin, E-Selectin, and the chemokine cascades that occur during endothelial cell inflammation [14][15][16][17][18]. The human adhesion molecules, ICAM-1 and VCAM-1, which are expressed at low density on normal endothelial cells, are upregulated with cytokines and therefore have provided a good model of inflammation in other investigations with cell-based or in vivo systems.…”

Section: Introductionmentioning

confidence: 99%

Circulating IgSF Proteins Inhibit Adhesion of Antibody Targeted Microspheres to Endothelial Inflammatory Ligands

Kerby

Urban

Mouallem

et al. 2009

Appl Biochem Biotechnol

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Proposed methods for detecting circulatory system disease include targeting ultrasound contrast agents to inflammatory markers on vascular endothelial cells. For antibody-based therapies, soluble forms of the targeted adhesion proteins of the immunoglobulin superfamily (IgSF) reduce adhesion yet were left unaccounted in prior reports. Microspheres labeled simply with a maximum level of antibodies can reduce the diagnostic sensitivity by adhering to proteins expressed normally at a low level, while sparsely coated particles may be rendered ineffective by circulating soluble forms of the targeted proteins. A new microdevice technique is applied to simultaneously measure the adhesion profile to a series of IgSF-protein-coated surfaces. In this investigation, we quantify the in vitro binding characteristics of 5-microm microspheres to oriented intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) protein-coated surfaces in the presence of human serum at physiological concentrations. Defined regions of a slide were coated with recombinant chimeric Fc-human ICAM-1 and VCAM-1 in variable ratios but constant total concentration. Monoclonal human anti-ICAM-1 or anti-VCAM-1 antibodies in competition with non-binding mouse anti-rabbit antibodies coat the microsphere surface at a constant surface density with variable yet controlled surface activities. Using multiple slide surface IgSF protein and microsphere antibody concentrations, an adhesion profile was developed for the microspheres with and without IgSF proteins from human serum, which demonstrated that exposure to serum reduced microsphere binding, on average, more than 50% compared to the no-serum condition.. The serum effects were limited to antibodies on the microsphere, since binding inhibition was reversed after rinsing serum from the system and fresh antibody-coated microspheres were introduced. This analysis quantifies the binding effects of soluble IgSF proteins from human serum on antibody-based targeted ultrasound detection and drug delivery methods.

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In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors

Cited by 75 publications

References 41 publications

How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers

How Carrier Size and Valency Modulate Receptor-Mediated Signaling: Understanding the Link between Binding and Endocytosis of ICAM-1-Targeted Carriers

Multifactorial determinants that govern nanoparticle uptake by human endothelial cells under flow

Circulating IgSF Proteins Inhibit Adhesion of Antibody Targeted Microspheres to Endothelial Inflammatory Ligands

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