T. Ouchi et al., DESIGN OF MACROMOLECULAR PRODRUG OF 5-FLUOROURACIL USING N-ACETYLPOLYGALACTOSAMINE AS A TARGETING CARRIER TO HEPATOMA, Reactive & functional polymers, 37(1-3), 1998, pp. 235-244
alpha-1,4-Polygalactosamine (PGA) purified from the culture fluid of P
aecilomyces sp. I-1 strain and N-acetylated alpha-1,4-polygalactosamin
e (NAPGA) are chitosan- and chitin-like biodegradable, compatible alph
a-1,,4-linked polysaccharides, respectively. Partially N-acetylated PG
A was found to show the stronger binding activity onto MH134Y hepatoma
cells than three kinds of normal lymphocytes, bone marrow, T and B ce
lls from the results of binding assay of C-14-50% N-acetylated PGA in
vitro. Since PGA and NAPGA have the unreducing end groups of galactosa
mine and N-acetyl galactosamine, respectively, they were suggested to
exhibit the receptor-mediated affinities to hepatoma cells. In order t
o provide the lysosomotropic macromolecular prodrug of fluorouracil (5
FU) having a targeting ability to hepatoma, we synthesized water-solub
le 6-O-carboxymethyl-NAPGA-immobilized 5FUs through Gly-Phe-Leu-Gly, m
onomethylene spacer groups. The obtained conjugate showed the cathepsi
n-B-susceptible release behavior of 5FU and then exhibited the stronge
r cytotoxic activity than free 5FU against HLE hepatoma cells in vitro
. (C) 1998 Elsevier Science B.V. All rights reserved.