Systemic fungal infections, a major problem in patients with certain malignancies, are most often treated with the polyene antibiotic Amphotericin B (AMB). This drug is efficacious but is also extremely toxic and is difficult to administer. We have previously demonstrated that the incorporation of AMB in phospholipid vesicles (liposomes) can markedly reduce its toxicity with no loss of anti fungal potency; this effect occurs both in vivo and in vitro. We now wish to elucidate the mechanisms underlying the increased selective toxicity (therapeutic index) of liposomal AMB. In order to ascertain the role of various fungal components in this process we will examine free or liposomal AMB induced ion permeabililty changes in yeast cells, in protoplasts and in liposomes prepared from yeast or mammalian lipids. We will examine the role of the structure and composition of the liposomes in terms of their ability to deliver AMB to yeast cells, yeast protoplasts or mammalian cells. We will determine if the selectivity of other polyene antibiotics can be enhanced in vitro and in vivo via incorporation in liposomes. Finally, we will use biophysical techniques to examine the mechanism of transfer of polyene antibiotics from donor liposomes to other membranes. These investigations will provide basic information on the mechanism of action of liposomal polyene antibiotics and will contribute to the development of improved liposomal carrier systems for therapy of fungal infections in cancer patients.
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