ANTITUMOR-ACTIVITY OF 5'-O-DIPALMITOYLPHOSPHATIDYL O-2'-DEOXY-1-BETA-D-ARABINO-PENTOFURANOSYLCYTOSINE IS ENHANCED BY LONG-CIRCULATING LIPOSOMALIZATION

We previously synthesized the 5'-O-diacylphosphatidyl derivative of no -2'-deoxy-1-beta-D-arabinopentofuranosylcytosine (CNDAC), a novel anti tumor nucleoside, and observed it to have a high antitumor activity. S ince this compound is readily incorporated into liposomal membranes, w e 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-circul ating liposomes composed of DPP-CNDAC, dipalmitoylphosphatidylcholine, cholesterol and palmityl-D-glucuronide (PGlcUA) (2:2:2:1 as a molar r atio), as well as liposomes containing dipalmitoylphosphatidylglycerol (DPPG) instead of palmityl-D-glucuronide and those composed of only D PP-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 use ful to enhance therapeutic efficacy. Furthermore, liposomal DPP-CNDAC reduced the acute toxicity, and liposomes containing PGlcUA showed mor e enhanced activities of reducing tumor growth and increasing the life time of the mice than liposomes containing DPPG, To obtain a higher th erapeutic efficacy, we injected long-circulating liposomal DPP-CNDAC 5 times. The tumor growth was suppressed to 13.2% (86.8% inhibition), a nd the survival time of the tumor-bearing mice increased to 128.5% wit h one completely cured mouse out of five. Next, the effect of DPP-CNDA C incorporation on the in vivo behavior of PGlcUA and DPPG liposomes w as examined by a non-invasive method using positron emission tomograph y (PET), Liposomes were labeled with [2-F-18]-2-fluoro-2-deoxy-D-gluco se, and administered to tumor-bearing mice. PET images and time-activi ty curves indicated that DPP-CNDAC/PGlcUA-liposomes tended to accumula te in tumor tissues a little bit more than DPP-CNDAC/DPPG-liposomes, a lthough the difference between the two kinds of liposomal distribution was not as marked as between PGlcUA and DPPG liposomes, suggesting th at DPP-CNDAC incorporation partly affected the liposomal behavior in v ivo but that the long-circulating character of PGlcUA-liposomes might not be fully abolished. Thus, the enhanced therapeutic efficacy of lon g circulating liposomalized DPP-CNDAC observed here may be due to pass ive targeting of DPP-CNDAC to the tumor tissue, making this formulatio n of DPP-CNDAC useful for cancer chemotherapy.