Albumin modified with mannose 6-phosphate: A potential carrier for selective delivery of antifibrotic drugs to rat and human hepatic stellate cells

The hallmark of liver fibrosis is an increased extracellular matrix deposit ion, caused by an activation of hepatic stellate cells (HSC). Therefore, th is cell type is an important target for pharmacotherapeutic intervention. A ntifibrotic drugs are not efficiently taken up by HSC or may produce unwant ed side-effects outside the liver. Cell-specific delivery can provide a sol ution to these problems, but a specific drug carrier for HSC has not been d escribed until now The mannose 6-phosphate/insulin-like growth factor II (M 6P/IGF-II) receptor, which is expressed in particular upon HSC during fibro sis, 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 ma nnose 6-phosphate (M6P) is taken up by HSC in fibrotic livers. A series of MGP(x)-modified albumins were synthetized: x = 2, 4, 10, and 28. Organ dist ribution studies were performed to determine total liver uptake. The hepati c uptake of M6P,HSA increased with increasing M6P density. M6P(x)-HSA with a low degree of sugar loading (x = 2-10) remained in the plasma and accumul ated for 9% +/- 0.5% or less in fibrotic rat livers. An increase in the mol ar ratio of M6P: HSA to 28:1 caused an increased liver accumulation to 59% +/- 9% of the administered dose. Furthermore, we determined quantitatively the in vivo intrahepatic distribution of M6P(x)-HSA using double-immunostai ning techniques. An increased substitution of M6P was associated with an in creased accumulation in HSC; 70% +/- 11% of the intrahepatic staining for M 6P(28)-HSA was found in HSC. We also demonstrate that M6P-modified bovine s erum albumin (BSA) accumulates in slices of normal and cirrhotic human live rs. After incubation of this neoglycoprotein with human tissue, the protein is found in nonparenchymal liver cells. Because M6P-modified albumins are taken up by HSC in fibrotic livers, this neoglycoprotein can be applied as a selective drug carrier for HSC. This technology may create new opportunit ies for the pharmacological intervention of liver fibrosis.