In order to provide a macromolecular
prodrug of
5-fluorouracil (
5FU) with reduced side-effects and exhibiting strong antitumor activity,
5FU was covalently linked to poly(
ethylene glycol) (PEG) via a
urethane or
urea bond. For the purpose of evaluating the release behavior of
5FU, the hydrolysis of the
urethane or
urea bond in the obtained conjugate of PEG-end capped with
5FU was investigated in vitro at 37 degrees C in aqueous
solution media. The survival effect for the conjugate was assessed in vivo against p388
lymphocytic leukemia in female CDF1 mice by intraperitoneal (i.p.)
transplantation/i.p. injection. The effects of a hydrophobic hexamethylene spacer group, the end group and the number n of
ethylene oxide (EO) units in PEG on the release behavior of
5FU and the survival effect were investigated. The release rate of
5FU from the 5FU-terminated PEG conjugates via
urethane or
urea bond was very fast. However, it became slow with increasing n of EO units in PEG and was depressed by the introduction of hydrophobic spacer group. The 5FU-terminated PEG conjugates obtained exhibited significant survival effects against
p388 leukemia mice i.p./i.p. Especially, the methoxy PEG (n = 113)/
urethane/hexamethylene/
urea/
5FU conjugate showed the strongest survival effect among the synthesized 5FU-capped PEG conjugates via
urethane or
urea bond compared to free
5FU against
p388 leukemia mice. These conjugates obtained did not display an acute toxicity even in high dose ranges.