TARGETING DELIVERY OF PROTEIN DRUGS BY CHEMICAL MODIFICATION

In vivo disposition profiles of protein derivatives having various chemical modifications were systematically compared in mice based on the clearance concept. Proteins such as bovine gamma-globulin (IgG), bovine serum albumin (BSA), superoxide dismutase (SOD), soybean trypsin inhibitor (STI), and chicken egg white lysozyme (LZM) were 1)conjugated with polyethylene glycol (PEG) and dextran to increase molecular size, 2) conjugated with carboxymethyl-dextran (CMD) and diethylaminoethyl-dextran (DEAED) or coupled with diaminohexane or succinic acid to introduce electric charges, and 3) modified with galactose (Gal) and mannose (Man) moieties to bestow an affinity for receptor-mediated endocytosis in cells. By applying these modifications, in vivo disposition features of proteins were extensively changed; i.e., in the case of SOD, conjugation with CMD and PEG prolonged its circulation half-life more than 100 times but cationized SOD showed remarkable accumulation on the surface of the liver tissue. In addition, specific targeting to the parenchymal cells of the liver was demonstrated in Gal-SOD, while, Man-SOD and succinylated SOD showed rapid uptake by the nonparenchymal cells. These results revealed the utility of chemical modification for controlling in vivo disposition of proteins.