Pharmacokinetics of succinylated proteins and dextran sulfate in mice: Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors

The disposition characteristics of three types of 111In-labeled succinylated proteins, succinylated Superoxide dismutase (Suc-SOD; Mol. Wt 34000), bovine serum albumin (Suc-BSA; Mol. Wt 70000) and uricase (Suc-UC; Mol. Wt 130000) and [14Qdextran sulfate (DS; Mol. Wt 8000) after intravenous injection were studied in mice. At a dose of 1 mg/kg, [111In]Suc-BSA and [111In]Suc-UC were taken up by the liver to a great extent whereas [111In]Suc-SOD was rapidly excreted into the urine without marked hepatic uptake. [111In]Suc-BSA was preferentially localized in non-parenchymal cells of the liver. Rapid urinary excretion was observed for [14C]DS, however, it accumulated in the liver. Hepatic uptake of [111In]Suc-BSA and [14C]DS was suppressed at a higher dose (100 mg/kg), suggesting a saturable uptake process. Pharmacokinetic analysis revealed that hepatic uptake clearances of [111In]Suc-BSA, [111In]Suc-UC and [14C]DS were 15.8-, 7.2- and 10.4-fold higher than that of [111In]Suc-SOD, respectively, at 1 mg/kg. Hepatic uptake of [111In]Suc-BSA was significantly inhibited by simultaneous administration of excess amounts of other negatively charged macromolecules, such as maleylated BSA (Mal-BSA), heparin, DS and polyinosinic acid (poly[I]), typical ligands for scavenger receptors. On the other hand, native BSA, cationized BSA (Cat-BSA), galactosylated and mannosylated BSA (Gal- and Man-BSA), carboxymethyl dextran (CM-dex) and polycytidylic acid (poly[C]) were not effective inhibitors. Thus, this is the first report that protein drugs can be targeted to liver non-parenchymal cells by direct succinylation through scavenger receptors in vivo. In addition, the importance of molecular weight or total number of anionic charges per protein molecule was suggested.