Alkylphospholipid liposomes: Preparation, properties and use in cancer research

The aim of this study was to design liposomes from alkylphospholipids and t o elucidate the benefits of this new galenic form of alkylphospholipids in experimental cancer chemotherapy. The preparation of liposomes made from al kylphosphocholines, in which the antitumor principle is part of the bilayer , is possible if cholesterol and a charged component are added. Alkylphosph olipid liposomes are remarkably stable in buffer and plasma. The direct cyt otoxic effects in vitro are dependent on the lipid used and on the liposoma l composition. Furthermore, alkylphospholipids liposomes are able to induce the release of such tumoricidal factors as nitric oxide and tumor necrosis factor from different macrophage cell lines. It was found that the biologi cal relevant properties could be changed by the incorporation of up to 10 m ol% of polyethylene glycol derivatives of phosphoethanolamine. As a result, the uptake of such sterically stabilized liposomes by macrophages was redu ced in vitro and in vivo compared to conventional alkylphospholipid liposom es. Alkylphospholipids in micellar solution or as liposomal formulation led to a remarkable tumor growth inhibition toward breast cancer xenografts wi th a clear preference toward estrogen receptor negative carcinomas. In para llel, the dose-limiting local side effects on gastrointestinal tract and re d blood cells clearly could be mitigated by using the liposomal formulation . Sterically stabilized alkylphospholipid liposomes were taken up by the mo nonuclear phagocyte system in a distinctly reduced amount leading in some c ases to an improved antitumor effect. Comparing all the investigated alkylp hospholipids, the new derivative octadecyl (1,1-dimethyl-4-piperidino-4-yl) -phosphate (D-21266) was the most powerful lipid, especially in liposomal f orm. These liposomes show in vitro the same activity as the micellar D-2126 6. Moreover, a superior effect in xenotransplanted MT3 breast cancer model could be demonstrated when the liposomes contained polyethylene glycol and the amount of cholesterol was reduced. Overall, we have concluded that alky lphospholipid liposomes should be seriously considered as an alternative to classical cytostatic drugs and to micellar alkyl- phospholipids for the cl inical use in breast carcinomas. (C) 1998 Prous Science. Ail rights reserve d.