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 Technolog
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- 作者：Kai Temming ; Marie Lacombe ; Paul van der Hoeven ; Jai Prakash ; Teresa Gonzalo ; Eli C. F. Dijkers ; Lá ; szló ; Orfi ; Gyorgy Ké ; ri ; Klaas Poelstra ; Grietje Molema ; Robbert J. Kok
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：September 2006
- 年：2006
- 卷：17
- 期：5
- 页码：1246 - 1255
- 全文大小：458K
- 年卷期：v.17,no.5(September 2006)
- ISSN：1520-4812
文摘
Endothelial cells play an important role in inflammatory disorders, as they control the recruitment of leukocytesinto inflamed tissue and the formation of new blood vessels. Activation of p38MAP kinase results in the productionof proinflammatory cytokines and the expression of adhesion molecules. P38MAP kinase inhibitors are thereforeconsidered important candidates for the treatment of inflammatory disorders. In the present study, we propose anovel strategy to counteract these processes by delivery of the p38MAP kinase inhibitor SB202190 into angiogenicendothelial 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 byconjugation of cyclic RGD-peptides via bifunctional polyethylene glycol linkers. The final products contained anaverage of nine SB202190 and six RGDPEG groups per albumin. The platinum-based linker displayed highstability in buffers and culture medium, but released SB202190 slowly upon competition with sulfur-containingligands like glutathione. RGDPEG-SB-HSA bound to 
v3-integrin expressing endothelial cells (human umbilicalcord vein endothelial cells) with low nanomolar affinity and was subsequently internalized. When HUVEC weretreated with TNF to induce inflammatory events, pretreatment with RGDPEG-SB-HSA partially inhibitedproinflammatory 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 counteractinflammation disorders such as rheumatoid arthritis.
v3-integrin expressing endothelial cells (human umbilicalcord vein endothelial cells) with low nanomolar affinity and was subsequently internalized. When HUVEC weretreated with TNF to induce inflammatory events, pretreatment with RGDPEG-SB-HSA partially inhibitedproinflammatory 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 counteractinflammation disorders such as rheumatoid arthritis.