Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

Beljaars, Leonie; Molema, Grietje; Schuppan, Detlef; Geerts, Albert; Bleser, PJ De; Weert, B; Meijer, Dirk K. F.; Poelstra, Klaas

doi:10.1074/jbc.275.17.12743

Cited by 136 publications

(107 citation statements)

References 52 publications

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“…In the future we will pursue this matter with more specific antifibrotic agents, also targeted to HSC by using our recently developed carriers for this cell type. 17,27 FIG. 12.…”

Section: Discussionmentioning

confidence: 99%

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Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

Melgert

2001

Hepatology

103

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“…In the future we will pursue this matter with more specific antifibrotic agents, also targeted to HSC by using our recently developed carriers for this cell type. 17,27 FIG. 12.…”

Section: Discussionmentioning

confidence: 99%

“…These liver slices still have their normal cell-cell contacts 17,18,26,27 and can be used to assess LPS-induced liver cell activation for 24 hours. 12,28 Dexamethasone covalently linked to Man 10 -HSA was able to inhibit the LPS-induced production of nitric oxide (NO) and TNF-␣ in a dose-dependent manner ( Fig.…”

Section: In Vitro Effects Of Dexa 5 -Man 10 -Hsamentioning

confidence: 99%

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

Melgert

2001

Hepatology

103

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“…To understand the molecular basis of these effects, structural information is required to fully delineate the binding sites for drugs and endogenous ligands. Such information will also be invaluable to efforts to exploit the carrier properties of HSA in the development of novel therapeutic reagents for drug targeting (8) or oxygen transport (9).…”

mentioning

confidence: 99%

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Petitpas¹,

Bhattacharya²,

Twine³

et al. 2001

Journal of Biological Chemistry

777

605

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Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determined the crystal structures at 2.5 Å-resolution of HSA-myristate complexed with the R-(؉) and S-(؊) enantiomers of warfarin, a widely used anticoagulant that binds to the protein with high affinity. The structures confirm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein-drug interaction. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amino acid side chains at the binding site, thus accounting for the relative lack of stereospecificity of the HSA-warfarin interaction. The conformation of the warfarin binding pocket is significantly altered upon binding of fatty acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid.

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“…The total radioactivity in each tissue was measured with a gamma counter (Riastar Gamma Counting System; PerkinElmer Life and Analytical Sciences, Boston, MA) and then corrected for blood-derived radioactivity in that tissue. This correction factor was calculated from biodistribution studies with HSA, a protein that remains in the circulation during the time frame of this experiment, as described previously (Beljaars et al, 2000).…”

Section: Design Of a Liver-selective Form Of Interleukin-10mentioning

confidence: 99%

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Rachmawati¹,

Reker‐Smit²,

Hooge³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Cytokines are considered a promising immunotherapy for chronic diseases, because of their potency and fundamental roles in pathological processes. However, their therapeutic use is limited because of their poor pharmacokinetics and pleiotropic effects in various organs. These problems may be overcome by cell-specific delivery of the cytokine. This approach involves chemical modification of the protein with homing devices that recognize receptors on target cells. The cytokine interleukin-10 (IL10) may be valuable as a therapeutic cytokine for patients with liver cirrhosis. However, its rapid renal elimination and general immunosuppressive activities limit therapeutic use. We therefore aim to target this cytokine in the liver, in particular to fibrogenic hepatic stellate cells (HSCs). We show that IL10 is successfully modified with mannose 6-phosphate (M6P), which is a homing device for the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor expressed on activated HSCs. Chemical modification did not diminish IL10 efficacy with regard to in vitro anti-inflammatory (lipopolysaccharide-stimulated tumor necrosis factor ␣ release) and antifibrotic (collagen deposition and degradation) activities. Biodistribution studies with radiolabeled M6P-IL10 and IL10 in rats with liver fibrosis showed that modification with M6P groups induced a shift in the distribution from the kidneys (IL10) to the liver (M6P-IL10). Hepatocellular binding of M6P-IL10 occurred via M6P/IGFII receptors and scavenger receptors, indicating that not only HSCs but also Kupffer and endothelial cells are target cells. IL10 did not bind to these receptors. We conclude that we prepared an active and liver-specific form of the cytokine IL10 that can be evaluated for its efficacy to treat liver diseases.

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Successful Targeting to Rat Hepatic Stellate Cells Using Albumin Modified with Cyclic Peptides That Recognize the Collagen Type VI Receptor

Cited by 136 publications

References 52 publications

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

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