Inhibition of L-selectin binding by polyacrylamide-based conjugates under defined flow conditions

Enders, Sven; Bernhard, Gesche; Zakrzewicz, Andreas; Tauber, Rudolf

doi:10.1016/j.bbagen.2007.06.015

Cited by 36 publications

(58 citation statements)

References 62 publications

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“…Surface plasmon resonance experiments were carried out on a BIAcore X instrument (GE Healthcare) at 25°C. The competitive selectin-ligand binding assay has been described in detail previously (20). In brief, selectin-IgG chimeras (R&D Systems) were immobilized on protein A coated Au nanoparticles (Biotrend) and passed over a standard ligand (20 mol% SiaLe x and 5 mol% Y-SO 3 − conjugated to polyacrylamide, Lectinity) immobilized on a sensor chip.…”

Section: Methodsmentioning

confidence: 99%

“…Regeneration of the surface was done by injection of 4 M MgCl 2 at 100 μL∕ min for 60 sec. Proteins were used at five concentrations (10,20,30,40, and 50 nM for C3 and 1, 1.56, 3.12, 6.25, and 10 nM for C5). Rate constants were calculated by using BIAevaluation software 4.1 assuming a 1∶1 mode of binding.…”

Section: Methodsmentioning

confidence: 99%

“…The assay was performed as previously described (20,38). In brief, HUVECs on cover slips were activated with TNF-α (human, 100 U∕mL, 5 h exposure, purchased from Alexis), and exposed to nearly physiological conditions in a parallel-plate flow chamber.…”

Section: Methodsmentioning

confidence: 99%

“…S1) that allows the determination of IC 50 values for inhibitory compounds over a large concentration range (pM-mM) (20,21). Initially, we analyzed the selectin specificity of dPGS.…”

mentioning

confidence: 99%

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Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dernedde

Rausch

Weinhart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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247

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Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of antiinflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.anti-inflammatory drug | complement inhibition | multiple target binding | multivalent selectin inhibitor | synthetic polymer

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…S1) that allows the determination of IC 50 values for inhibitory compounds over a large concentration range (pM-mM) (20,21). Initially, we analyzed the selectin specificity of dPGS.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dernedde

Rausch

Weinhart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

247

294

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“…The vessel wall is modeled by either coating of biomolecules or growth of cells on one surface of the flow chamber 3 . Particles [4][5][6][7] or cells [8][9][10][11][12][13][14][15][16] are then flowed in at desired range of flow rates to quantify the number of adhering particles under various shear rates.…”

Section: Introductionmentioning

confidence: 99%

Generation of Shear Adhesion Map Using SynVivo Synthetic Microvascular Networks

Prabhakarpandian

Pant

2014

JoVE

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Cell/particle adhesion assays are critical to understanding the biochemical interactions involved in disease pathophysiology and have important applications in the quest for the development of novel therapeutics. Assays using static conditions fail to capture the dependence of adhesion on shear, limiting their correlation with in vivo environment. Parallel plate flow chambers that quantify adhesion under physiological fluid flow need multiple experiments for the generation of a shear adhesion map. In addition, they do not represent the in vivo scale and morphology and require large volumes (~ml) of reagents for experiments. In this study, we demonstrate the generation of shear adhesion map from a single experiment using a microvascular network based microfluidic device, SynVivo-SMN. This device recreates the complex in vivo vasculature including geometric scale, morphological elements, flow features and cellular interactions in an in vitro format, thereby providing a biologically realistic environment for basic and applied research in cellular behavior, drug delivery, and drug discovery. The assay was demonstrated by studying the interaction of the 2 µm biotin-coated particles with avidin-coated surfaces of the microchip. The entire range of shear observed in the microvasculature is obtained in a single assay enabling adhesion vs. shear map for the particles under physiological conditions. Video LinkThe video component of this article can be found at

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Shell Cleavable Dendritic Polyglycerol Sulfates Show High Anti‐Inflammatory Properties by Inhibiting L‐Selectin Binding and Complement Activation

Reimann

Gröger

Kühne

et al. 2015

Adv Healthcare Materials

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A new class of fully synthetic shell cleavable multivalent polysulfates is prepared by introducing degradable linkers into a stable biocompatible dendritic polyglycerol scaffold and subsequent sulfation. The sulfated polymers show different degradation profiles, low anticoagulant and high anti-inflammatory properties, are able to efficiently bind to L-selectin and inhibit the complement activation at very low concentrations in vitro.

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Inhibition of L-selectin binding by polyacrylamide-based conjugates under defined flow conditions

Cited by 36 publications

References 62 publications

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Generation of Shear Adhesion Map Using SynVivo Synthetic Microvascular Networks

Shell Cleavable Dendritic Polyglycerol Sulfates Show High Anti‐Inflammatory Properties by Inhibiting L‐Selectin Binding and Complement Activation

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