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Department of
*
Pharmacokinetics and Drug Delivery and
Pathology and Laboratory Medicine, Medical Biology Section, Groningen University Institute for Drug Exploration, Groningen, The Netherlands;
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands; and
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands
In chronic inflammatory diseases, the endothelium is an attractive
target for pharmacological intervention because it plays an important
role in leukocyte recruitment. Hence, inhibition of endothelial cell
activation and consequent leukocyte infiltration may improve
therapeutic outcome in these diseases. We report on a drug targeting
strategy for the selective delivery of the anti-inflammatory drug
dexamethasone to activated endothelial cells, using an
E-selectin-directed drug-Ab conjugate. Dexamethasone was covalently
attached to an anti-E-selectin Ab, resulting in the so-called
dexamethasone-anti-E-selectin conjugate. Binding of the conjugate
to E-selectin was studied using surface plasmon resonance and
immunohistochemistry. Furthermore, internalization of the conjugate was
studied using confocal laser scanning microscopy and
immuno-transmission electron microscopy. It was demonstrated that the
dexamethasone-anti-E-selectin conjugate, like the unmodified
anti-E-selectin Ab, selectively bound to TNF-
-stimulated
endothelial cells and not to resting endothelial cells. After binding,
the conjugate was internalized and routed to multivesicular bodies,
which is a lysosome-related cellular compartment. After intracellular
degradation, pharmacologically active dexamethasone was released, as
shown in endothelial cells that were transfected with a
glucocorticoid-responsive reporter gene. Furthermore, intracellularly
delivered dexamethasone was able to down-regulate the proinflammatory
gene IL-8. In conclusion, this study demonstrates the possibility to
selectively deliver the anti-inflammatory drug dexamethasone into
activated endothelial cells, using an anti-E-selectin Ab as a
carrier molecule.
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