Liposomal sustained-release delivery systems for intravenous injection. IV. Antitumor activity of newly synthesized lipophilic 1-beta-D-arabinofuranosylcytosine prodrug-bearing liposomes.

Abstract

A lipophilic prodrug of 1-β-D-arabinofuranosylcytosine (Ara-C), namely N4-[N-(cholesteryl-oxycarbonyl)glycyl]-Ara-C (COCG-Ara-C), was synthesized and its antitumor activity in a liposome-entrapped form was studied. COCG-Ara-C showed an increaesd lipophilicity and almost complete entrapment in liposomes. COCG-Ara-C was hydrolyzed to the parent drug chemically, but the hydrolysis was accelerated in the presence of mouse, rat and human plasma. The in vitro cytoxicity of the prodrug against P 388 leukemia was approximately one-fifth that of Ara-C and four times that of N4-behenoyl-Ara-C (BHAC). For in vivo antitumor activity tests, unilamellar vesicles composed of egg phosphatidylcholine (PC), egg sphingomyelin (SM) and COCG-Ara-C in a molar ratio of 7 : 3 : X (X=0-2.0) were prepared by the combination of controlled dialysis and sequential extrusion. The vesicle size ranged from 108±18 nm to 124±18 nm. In all the antitumor activity studies, chemotherapy was performed intravenously. The antitumor activity of COCG-Ara-C-bearing liposomes against intraperitoneally- or intravenously-inoculated mouse L 1210 leukemia was clearly superior to those of Ara-C and BHAC aqueous solutions. The efficacy of COCG-Ara-C against L 1210 leukemia was dependent upon the dosage form : regardless of implantation route, liposomal COCG-Ara-C showed a more potent activity than free COCG-Ara-C (aqueous solution). Prodrug-bearing liposomes also inhibited the growth of a human lung adenocarcinoma A 549 xenograft implanted under the renal capsule more efficiently than did Ara-C and BHAC aqueous solutions. These results suggest the potential usefulness of COCG-Ara-C-bearing liposomes in cancer chemotherapy.