Selective targeting of pentoxifylline to hepatic stellate cells using a novel platinum-based linker technology

Gonzalo, Teresa; Talman, Eduard G.; Ven, Anke van de; Temming, Kai; Greupink, Rick; Beljaars, Leonie; Reker‐Smit, Catharina; Meijer, Dirk K. F.; Molema, Grietje; Poelstra, Klaas; Kok, Robbert J.

doi:10.1016/j.jconrel.2005.12.010

Cited by 48 publications

(42 citation statements)

References 22 publications

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“…Release of SB202190 was triggered by competition with sulfur ligands like glutathione at intracellular concentration. We have found the same release mechanism for other drug-ULS conjugates (Prakash et al, submitted) (24).…”

Section: Discussionsupporting

confidence: 81%

“…We concluded that drug-ULS conjugates have no apparent toxicity despite their similarity to cisplatin. The same conclusion has been drawn for other ULS-containing drug-targeting conjugates that have been developed in our lab for the targeting to hepatic stellate cells (24) or kidney tubular cells (Prakash et al, submitted).…”

Section: Discussionsupporting

confidence: 70%

“…Our hypothesis that SB-ULS preferably binds to sulfur groups in the carrier is supported by the finding that pentoxifyllin-ULS/albumin conjugation ratios increased when HSA was first modified with a thiocarbonylcontaining targeting ligand (24). Similarly, elevated drug-ULS/ carrier ratios were found when the kidney-selective carrier lysozyme was modified with extra methionine groups (J. Prakash et al, submitted).…”

Section: Discussionmentioning

confidence: 59%

“…Since aromatic nitrogens are present in many drug structures, our approach is applicable to many other drugs besides SB202190. We have recently reported on a similar linkage approach for the delivery of pentoxifyllin to hepatic stellate cells (24), and several other conjugates are under investigation.…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2006

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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 R 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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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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

et al. 2006

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“…We recently developed a versatile linking technology, the so-called Universal Linkage System (ULS), for the coupling of drugs to carrier systems, 20,21,23,24 which we now have applied for the conjugation of the Rho kinase inhibitor Y27632 to LZM. We investigated the potential activity of Y27632-LZM in the ischemia-reperfusion (I/R) injury model and demonstrated both enhanced activity and increased selectivity of the tubular-targeted Rho kinase inhibitor.…”

mentioning

confidence: 99%

Inhibition of Renal Rho Kinase Attenuates Ischemia/Reperfusion-Induced Injury

Prakash

Borst

Lacombe³

et al. 2008

Journal of the American Society of Nephrology

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The Rho kinase pathway plays an important role in dedifferentiation of epithelial cells and infiltration of inflammatory cells. For testing of the hypothesis that blockade of this cascade within the kidneys might be beneficial in the treatment of renal injury the Rho kinase inhibitor, Y27632 was coupled to lysozyme, a low molecular weight protein that is filtered through the glomerulus and is reabsorbed in proximal tubular cells. Pharmacokinetic studies with Y27632-lysozyme confirmed that the conjugate rapidly and extensively accumulated in the kidney. Treatment with Y27632-lysozyme substantially inhibited ischemia/reperfusion-induced tubular damage, indicated by reduced staining of the dedifferentiation markers kidney injury molecule 1 and vimentin, and increased E-cadherin relative to controls. Rho kinase activation was inhibited by Y27632-lysozyme within tubular cells and the interstitium. Y27632-lysozyme also inhibited inflammation and fibrogenesis, indicated by a reduction in gene expression of monocyte chemoattractant protein 1, procollagen I␣1, TGF-␤1, tissue inhibitor of metalloproteinase 1, and ␣-smooth muscle actin. Immunohistochemistry revealed reduced macrophage infiltration and decreased expression of ␣-smooth muscle actin, collagen I, collagen III, and fibronectin. In contrast, unconjugated Y27632 did not have these beneficial effects but instead caused systemic adverse effects, such as leukopenia. Neither treatment improved renal function in the bilateral ischemia/reperfusion model. In conclusion, the renally targeted Y27632-lysozyme conjugate strongly inhibits tubular damage, inflammation, and fibrogenesis induced by ischemia/reperfusion injury.

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Hepatic Fibrosis

Bataller¹,

Brenner²

2009

The Liver

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Selective targeting of pentoxifylline to hepatic stellate cells using a novel platinum-based linker technology

Cited by 48 publications

References 22 publications

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

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

Inhibition of Renal Rho Kinase Attenuates Ischemia/Reperfusion-Induced Injury

Hepatic Fibrosis

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