ABSTRACT
We studied the liposome formulation characteristics of eight new lipophilic antitumour agents that have demonstrated a broad spectrum of antitumour activity in preclinical in vitro and in vivo screening models. Multilamellar vesicles were prepared by using standard evaporation/hydration methods. The drug to lipid weight ratio was 1:15 in all cases. Different combinations of DMPC, DMPG and cholesterol were used. The quality of the liposomal formulations was evaluated by calculating the percentage drug bound to the liposome phase and assessing the morphology of the liposome phase by optic microscopy, to rule out the presence of drug crystals or drug/lipid microaggregates. Good liposomal preparations were obtained with hexamethylmelamine, penclomedine, mitindomide, and fazarabine. However, with taxol, batracylin, trimelamol, and diaziquone, the presence of crystals of free drug or microaggregates of lipid/drug complex was observed in all preparations, independently of lipid composition. In general, mixtures of DMPC:DMPG at a molar ratio between 7:3 and 9:1, and the addition of 5 per cent cholesterol (w/w) gave the optimal results. In vitro cytotoxicity studies of free and liposomal drugs against L1210 cells showed changes in both directions after liposome entrapment, thus suggesting that liposome entrapment may alter drug cellular uptake or may result in chemical modifications of the entrapped drug. Because of the limited number of compounds studied we were unable to identify general chemical characteristics required for an enhanced liposome formation and drug entrapment.
