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Cellular handling of a dexamethasone-anti-E-selectin immunoconjugate by activated endothelial cells: Comparison with free dexamethasone

Kok, RJ., Asgeirsdottir, SA., Meijer, DKF. & Molema, G., Nov-2002, In : Pharmaceutical Research. 19, 11, p. 1730-1735 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • RJ Kok
  • SA Asgeirsdottir
  • DKF Meijer
  • G Molema

Purpose. For selective inhibition of endothelial cell activation in chronic inflammation, we have developed a dexamethasone-anti-E-selectin immunoconjugate. The present study was performed to evaluate the cellular handling of this immunoconjugate by activated primary endothelial cells and to compare its drug delivery capacity with free dexamethasone.

Methods. The binding, uptake, and degradation of I-125-radiolabeled dexamethasone-anti-E-selectin immunoconjugate by TNFalpha-activated endothelial cells were studied for different time periods and at different concentrations, as well as in the presence of inhibitors for E-selectin binding and lysosomal degradation. Its drug delivery capacity was compared with the uptake of unconjugated H-3-labeled dexamethasone.

Results. The immunoconjugate was internalized by E-selectin expressing activated endothelial cells and degraded in the lysosomal compartment. The receptor-mediated binding and uptake was saturable, implying a maximal attainable intracellular concentration of the drug. In contrast, free dexamethasone entered both resting and activated endothelial cells by passive diffusion.

Conclusions. The dexamethasone-anti-E-selectin immunoconjugate is capable of selective delivering the coupled drug into activated endothelial cells. This targeting concept enables disease-induced drug delivery in which intracellular concentrations can be reached comparable with those obtained after incubation with 3 muM dexamethasone.

Original languageEnglish
Pages (from-to)1730-1735
Number of pages6
JournalPharmaceutical Research
Volume19
Issue number11
Publication statusPublished - Nov-2002

    Keywords

  • drug targeting, immunoconjugate, activated endothelial cells, lysosomal degradation, chronic inflammation, glucocorticoids, NF-KAPPA-B, INFLAMMATORY DISEASES, MOLECULES, ALBUMIN

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