Delivery of the p38 MAPkinase inhibitor SB202190 to angiogenic endothelial cells

Development of novel RGD-equipped and PEGylated drug-albumin conjugates using platinum(II)-based drug linker technology

Kai Temming, Marie Lacombe, Paul Van Der Hoeven, Jai Prakash, Teresa Gonzalo, Eli C F Dijkers, L. Őrfi, G. Kéri, Klaas Poelstra, Grietje Molema, Robbert J. Kok

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Endothelial cells play an important role in inflammatory disorders, as they control the recruitment of leukocytes into inflamed tissue and the formation of new blood vessels. Activation of p38MAP kinase results in the production of proinflammatory cytokines and the expression of adhesion molecules. P38MAP kinase inhibitors are therefore considered important candidates for the treatment of inflammatory disorders. In the present study, we propose a novel strategy to counteract these processes by delivery of the p38MAP kinase inhibitor SB202190 into angiogenic endothelial cells. A drug-targeting conjugate was developed by conjugation of SB202190 to human serum albumin (HSA) using a novel platinum-based linker. Specificity for angiogenic endothelial cells was introduced by conjugation of cyclic RGD-peptides via bifunctional polyethylene glycol linkers. The final products contained an average of nine SB202190 and six RGDPEG groups per albumin. The platinum-based linker displayed high stability in buffers and culture medium, but released SB202190 slowly upon competition with sulfur-containing ligands like glutathione. RGDPEG-SB-HSA bound to αv3-integrin expressing endothelial cells (human umbilical cord vein endothelial cells) with low nanomolar affinity and was subsequently internalized. When HUVEC were treated with TNF to induce inflammatory events, pretreatment with RGDPEG-SB-HSA partially inhibited proinflammatory gene expression (IL-8, E-selectin; 30% inhibition) and secretion of cytokines (IL-8, 34% inhibition). We conclude that the developed RGDPEG-SB-HSA conjugates provide a novel means to counteract inflammation disorders such as rheumatoid arthritis.

Original languageEnglish
Pages (from-to)1246-1255
Number of pages10
JournalBioconjugate Chemistry
Volume17
Issue number5
DOIs
Publication statusPublished - Sep 2006

Fingerprint

Endothelial cells
Platinum
Serum Albumin
Albumins
Endothelial Cells
Technology
Phosphotransferases
Interleukin-8
Pharmaceutical Preparations
Cytokines
Cyclic Peptides
E-Selectin
Umbilical Cord
Human Umbilical Vein Endothelial Cells
Drug Delivery Systems
Sulfur
Integrins
Glutathione
Blood Vessels
Culture Media

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Delivery of the p38 MAPkinase inhibitor SB202190 to angiogenic endothelial cells : Development of novel RGD-equipped and PEGylated drug-albumin conjugates using platinum(II)-based drug linker technology. / Temming, Kai; Lacombe, Marie; Van Der Hoeven, Paul; Prakash, Jai; Gonzalo, Teresa; Dijkers, Eli C F; Őrfi, L.; Kéri, G.; Poelstra, Klaas; Molema, Grietje; Kok, Robbert J.

In: Bioconjugate Chemistry, Vol. 17, No. 5, 09.2006, p. 1246-1255.

Research output: Contribution to journalArticle

Temming, Kai ; Lacombe, Marie ; Van Der Hoeven, Paul ; Prakash, Jai ; Gonzalo, Teresa ; Dijkers, Eli C F ; Őrfi, L. ; Kéri, G. ; Poelstra, Klaas ; Molema, Grietje ; Kok, Robbert J. / Delivery of the p38 MAPkinase inhibitor SB202190 to angiogenic endothelial cells : Development of novel RGD-equipped and PEGylated drug-albumin conjugates using platinum(II)-based drug linker technology. In: Bioconjugate Chemistry. 2006 ; Vol. 17, No. 5. pp. 1246-1255.
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AU - Gonzalo, Teresa

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AU - Őrfi, L.

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AU - Poelstra, Klaas

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