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Titolo:
Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells
Autore:
Beljaars, L; Molema, G; Weert, B; Bonnema, H; Olinga, P; Groothuis, GMM; Meijer, DKF; Poelstra, K;
Indirizzi:
Univrechtingen, Dept Pharmacokinet & Drug Delivery, Ctr Pharm, Groningen Ut Univ Groningen Groningen Netherlands NL-9713 AV Ctr Pharm, Groningen Ut
Titolo Testata:
HEPATOLOGY
fascicolo: 5, volume: 29, anno: 1999,
pagine: 1486 - 1493
SICI:
0270-9139(199905)29:5<1486:AMWM6A>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
GROWTH-FACTOR-II; BILE-DUCT OBSTRUCTION; FAT-STORING CELLS; LIVER SLICES; ITO CELL; FACTOR-BETA-1 PRECURSOR; MONOCLONAL-ANTIBODIES; RECEPTOR EXPRESSION; BILIARY FIBROSIS; MEMBRANE LECTINS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
53
Recensione:
Indirizzi per estratti:
Indirizzo: Beljaars, L Univrechtingen,ndspt Pharmacokinet & Drug Delivery, Ctr Pharm,Groningen Ut Univ Groningen Ant Deusinglaan 1 Groningen Netherlands NL-9713 AV
Citazione:
L. Beljaars et al., "Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells", HEPATOLOGY, 29(5), 1999, pp. 1486-1493

Abstract

The hallmark of liver fibrosis is an increased extracellular matrix deposition, caused by an activation of hepatic stellate cells (HSC). Therefore, this cell type is an important target for pharmacotherapeutic intervention. Antifibrotic drugs are not efficiently taken up by HSC or may produce unwanted side-effects outside the liver. Cell-specific delivery can provide a solution to these problems, but a specific drug carrier for HSC has not been described until now The mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II) receptor, which is expressed in particular upon HSC during fibrosis, may serve as a target-receptor for a potential carrier. The aim of the present study was to examine if human serum albumin (HSA) modified with mannose 6-phosphate (M6P) is taken up by HSC in fibrotic livers. A series ofMGP(x)-modified albumins were synthetized: x = 2, 4, 10, and 28. Organ distribution studies were performed to determine total liver uptake. The hepatic uptake of M6P,HSA increased with increasing M6P density. M6P(x)-HSA witha low degree of sugar loading (x = 2-10) remained in the plasma and accumulated for 9% +/- 0.5% or less in fibrotic rat livers. An increase in the molar ratio of M6P: HSA to 28:1 caused an increased liver accumulation to 59%+/- 9% of the administered dose. Furthermore, we determined quantitativelythe in vivo intrahepatic distribution of M6P(x)-HSA using double-immunostaining techniques. An increased substitution of M6P was associated with an increased accumulation in HSC; 70% +/- 11% of the intrahepatic staining for M6P(28)-HSA was found in HSC. We also demonstrate that M6P-modified bovine serum albumin (BSA) accumulates in slices of normal and cirrhotic human livers. After incubation of this neoglycoprotein with human tissue, the protein is found in nonparenchymal liver cells. Because M6P-modified albumins aretaken up by HSC in fibrotic livers, this neoglycoprotein can be applied asa selective drug carrier for HSC. This technology may create new opportunities for the pharmacological intervention of liver fibrosis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 08:42:48