Lipophilic arabinofuranosyl cytosine derivatives in liposomes.

Highly lipophilic drugs can be used therapeutically only by the addition of possibly toxic solubilizing agents or by development of complex pharmaceutical formulations. One way of overcoming these disadvantages is the incorporation of such drugs into the bilayer matrix of phospholipid liposomes. To this end, we chose the approach of chemical transformation of water-soluble nucleosides of known cytotoxic properties into lipophilic drugs or prodrugs. Due to their insolubility, we developed formulations that can be used for intravenous applications in which the lipophilic molecules are incorporated into lipid bilayer membranes of small liposomes. We chose 1-beta-d-arabinofuranosylcytosine (ara-C) as a cytotoxic nucleoside, and we demonstrated that N(4)-acyl derivatives of ara-C were active in vivo in various murine tumor models as liposomal formulations. However, the protection against enzymatic deamination was only partially achieved and was insufficient for significant improvement of cytotoxic properties. Thus, we synthesized a new class of N(4)-alkyl-ara-C derivatives. The most effective derivative, N(4)-octadecyl-ara-C (NOAC), is highly lipophilic and extremely resistant toward deamination. NOAC exerts excellent antitumor activity after oral and parenteral therapy. The activity of NOAC against freshly explanted clonogenic cells from human tumors was determined and compared with conventional antitumor agents. NOAC was used in two liposomal preparations, a stable lyophilized and a freshly prepared liquid formulation. Both formulations inhibited tumor colony formation equally in a concentration-dependent fashion. At optimal conditions, liposomal NOAC had significantly better activity compared with the clinically used drugs cisplatin, doxorubicin, 5-fluorouracil, gemcitabine, mitomycin C, and etoposide. Furthermore, in a hematopoietic stem cell assay, NOAC was less toxic than ara-C and doxorubicin by factors ranging from 2.5 to 200, indicating that this drug is well tolerated at high doses.