Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Autitumor Activity of 5'-O-Dipalmitoylphosphatidyl 2'-C-Cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine Is Enhanced by Long-Circulating Liposomalization
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1998 Volume 21 Issue 7 Pages 766-771


We previously synthesized the 5'-O-diacylphosphatidyl derivative of 2'-C-cyano-2'-deoxy-1-β-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-glu-curonide and those composed of only DPP-CNDAC, were injected intravenously into Meth A sarcoma-bearing mice, DPP-CNDAC showed suppression of tumor grouwth, 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 [2-18F]-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.

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