DESIGN OF LYSOSOMOTROPIC MACROMOLECULAR PRODRUG OF DOXORUBICIN USING N-ACETYL-ALPHA-1,4-POLYGALACTOSAMINE AS A TARGETING CARRIER TO HEPATOMA TISSUE

alpha-1,4-Polygalactosamine (PGA) and N-acetylated alpha-1,4-polygalac tosamine (NAPGA) are chitosan- and chitin-like biodegradable alpha-1,4 -linked polysaccharides, respectively. Radioactivity of C-14-50% N-ace tylated PGA injected into hepatomized mice, was found to accumulate mo re in the liver, kidney, ileum and hepatoma tumor tissues, compared wi th other organs. To provide a lysosomotropic macromolecular prodrug of doxorubicin (DXR) targeted to hepatoma tumor tissue, DXR was immobili zed on water-soluble 6-O-carboxymethyl(CM)-NAPGA by Gly-Phe-Leu-Gly sp acer groups (CM-NAPGA/Gly-Phe-Leu-Gly/DXR conjugate). The conjugate sh owed cathepsin B susceptible DXR release behavior and exhibited remark able survival effects in mice bearing MH134Y hepatoma implanted by sub cutaneous (s.c.) implantation/intravenous (i.v.) injection, compared w ith free DXR and CM-NAPGA-immobilized DXRs with pentamethylene spacer groups (CM-NAPGA/C-5/DXR conjugate).