Small unilamellar stealth monensin liposomes (SMLs) were prepared from multilamellar liposomes (MLVs). The MLVs were prepared by using dipalmitoyl phosphatidylcholine (DPPC), cholesterol, distearoyl glycerophosphoethanolamine coupled to poly(ethylene glycol) (DSPE-PEG) and stearylamine in the molar ratio of 10:5:1.4:1.4 (32.8 mM total lipid). The encapsulation efficiencies of monensin in MLVs and small unilamellar vesicles (SUVs) was 6x10++(-6) and 10(-7) M, respectively. The stability of SMLs was studied at 4 degrees C. The amount of leakage of monensin from SMLs was less than 20% after four weeks of storage. The in vitro release of monensin from SMLs in human serum was determined, and t1/2 was found to be 10 h. Pharmacokinetic studies on SMLs were carried out in BALB/c mice. More than 20% of SMLs remained in blood circulation after 24 h. SMLs increased the uptake of adriamycin (AM) in HL-60-resistant cells by more than two fold, compared to monensin in solution. SMLs potentiated the effect of AM against both sensitive and resistant HL-60 cells (six- and tenfold potentiation, respectively) and human LOVO tumor cells (four- and 200-fold potentiation, respectively). However, the highest potentiation was observed against resistant human breast tumor MCF7 cells, and was found to be 2400 times in comparison to AM alone. Transmission electron microscopic (TEM) studies carried out with HL-60-resistant tumor cells incubated with SMLs showed that SMLs caused dilation of the golgi of tumor cells within 10 min. The dilation of golgi was reversible after reincubation of the cells in fresh medium. SMLs showed considerable potential as a potentiator in combination with AM in overcoming drug resistance.