Amphotericin B−Dipalmitoyl Phosphatidyl Glycerol Interactions Responsible for the Reduced Toxicity of Liposomal Formulations: A Monolayer Study

Abstract

Mixtures of amphotericin B (AmB) and dipalmitoyl phosphatidyl glycerol (DPPG) were studied as floating Langmuir monolayers at the air/water interface. The films were analyzed using surface pressure−area (π−A) isotherms and compressional modulus−surface pressure (Cs-1−π) plots in addition to Brewster angle microscopy. The film components were found to interact with each other with the strongest interactions occurring at the ca. 2:1 AmB:DPPG mixed film composition (XAmB = 0.66), suggesting the formation of stable complexes composed of two horizontally oriented AmB molecules and one vertically oriented DPPG molecule. It has been suggested that the interactions between AmB and the phospholipid may compete in vivo with those between the antibiotic molecules and cellular membrane sterols. The toxic effects of AmB formulations containing free AmB (Fungizone) are thought to be due to the presence of free drug molecules that can interact with cellular membrane sterols, forming channels responsible for the observed toxicity. In liposomal AmB formulations on the other hand, AmB molecules are “immobilized” by their interactions with liposomal phospholipids, and therefore, are not as toxic to host cells.