We previously synthesized the 5'-O-diacylphosphatidyl derivative of 2'-C-cyano-2'-deoxy-1-beta-D-arabino-pentofuranosylcytosine (
CNDAC), a novel antitumor
nucleoside, and observed it to have a high antitumor activity. Since this compound is readily incorporated into liposomal membranes, we liposomalized the compound using a formulation for conventional and long-circulating
liposomes, and investigated the antitumor activity of liposomal 5'-O-dipalmitoylphosphatidyl
CNDAC (
DPP-CNDAC). Long-circulating
liposomes composed of
DPP-CNDAC,
dipalmitoylphosphatidylcholine,
cholesterol and palmityl-D-
glucuronide (
PGlcUA) (2:2:2:1 as a molar ratio), as well as
liposomes containing
dipalmitoylphosphatidylglycerol (
DPPG) instead of palmityl-D-
glucuronide and those composed of only
DPP-CNDAC, were injected intravenously into Meth A
sarcoma-bearing mice.
DPP-CNDAC showed suppression of
tumor growth, whereas
CNDAC did not at the same concentration, suggesting that 5'-phosphatidylation is useful to enhance therapeutic efficacy. Furthermore, liposomal
DPP-CNDAC reduced the acute toxicity, and
liposomes containing
PGlcUA showed more enhanced activities of reducing
tumor growth and increasing the lifetime of the mice than
liposomes containing
DPPG. To obtain a higher therapeutic efficacy, we injected long-circulating liposomal
DPP-CNDAC 5 times. The
tumor growth was suppressed to 13.2% (86.8% inhibition), and the survival time of the
tumor-bearing mice increased to 128.5% with one completely cured mouse out of five. Next, the effect of
DPP-CNDAC incorporation on the in vivo behavior of
PGlcUA and
DPPG liposomes was examined by a non-invasive method using positron emission tomography (PET).
Liposomes were labeled with [2-(18)F]-
2-fluoro-2-deoxy-D-glucose, and administered to
tumor-bearing mice. PET images and time-activity curves indicated that
DPP-CNDAC/
PGlcUA-
liposomes tended to accumulate in
tumor tissues a little bit more than
DPP-CNDAC/
DPPG-
liposomes, although the difference between the two kinds of liposomal distribution was not as marked as between
PGlcUA and
DPPG liposomes, suggesting that
DPP-CNDAC incorporation partly affected the liposomal behavior in vivo but that the long-circulating character of
PGlcUA-
liposomes might not be fully abolished. Thus, the enhanced therapeutic efficacy of long circulating liposomalized
DPP-CNDAC observed here may be due to passive targeting of
DPP-CNDAC to the
tumor tissue, making this formulation of
DPP-CNDAC useful for
cancer chemotherapy.