Design of Lysosomotropic Macromolecular Prodrug of Doxorubicin Using N-Acetyl-α-1,4-Polygalactosamine as a Targeting Carrier to Hepatoma Tissue

α-1,4-Polygalactosamine (PGA) and N-acetylated α-1,4-polygalactosamine (NAPGA) are chitosan- and chitin-like biodegradable α-1,4-linked polysaccharides, respectively. Radioactivity of 14C-50% N-acetylated PGA injected into hepatomized mice, was found to accumulate more in the liver, kidney, ileum and hepatoma tumor tissues, compared with other organs. To provide a lysosomotropic macromolecular prodrug of doxorubicin (DXR) targeted to hepatoma tumor tissue, DXR was immobilized on water-soluble 6-O-carboxymethyl(CM)-NAPGA by Gly-Phe-Leu-Glyspacer groups (CM-NAPGA/Gly-Phe-Leu-Gly/DXR conjugate). The conjugate showed cathepsin B susceptible DXR release behavior and exhibited remarkable survival effects in mice bearing MH134Y hepatoma implanted by subcutaneous (s.c.) implantation/intravenous (i.v.) injection, compared with free DXR and CM-NAPGA-immobilized DXRs with pentamethylene spacer groups (CM-NAPGA/C5/DXR conjugate).