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 alpha(v3)-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.