Antiproliferative and anticontractile effects of liposome encapsulated fluoroorotate

Incorporation of fluoroorotate into liposomes increases its growth inhibitory potency for rabbit dermal fibroblasts 30-fold. The optimal lipid composition of the liposomes is dipalmitoylphosphatidylglycerol:cholesterol (67:33). Liposomes prepared by reverse phase evaporation without extrusion are the optimal liposomes for delivery. Fluoroorotate, like other RNA directed fluoropyrimidines, inhibits the contractility of rabbit dermal fibroblasts. The effect is greatest when the cells are exposed to the drug for the 48-72 hr immediately prior to measurement of cell contractility. Encapsulation of fluoroorotate increases its anticontractile potency 10-fold. The anticontractile effects of both free and encapsulated fluoroorotate on the cells last at least 12 days. Leakage studies suggest that the loss of drug from the liposomes under storage conditions will be quite low. Leakage studies also confirm that serum will accelerate the loss of drug from the liposomes and that sonicated liposomes leak much more rapidly than larger liposomes. However, the large difference between egg phosphatidylglycerol and dipalmitoylphosphatidylglycerol liposomes for drug delivery is not explained by leakage studies. These results suggest that encapsulated fluoroorotate may be a useful adjunct to surgery for treatment of proliferative vitreoretinopathy.