Adriamycin-liposome interactions: A magnetic resonance study of the differential effects of cardiolipin on drug-induced fusion and permeability

Abstract

Nuclear magnetic resonance and electron spin resonance spectroscopy were utilized to measure the effects of adriamycin on the fusion rates and permeability characteristics of dimyristoylphosphatidylcholine (DMPC) liposomes containing small amounts of other lipids. Liposomes of pure DMPC in the presence or absence of adriamycin at a molar ratio of 100:1 showed little or no fusion. Incorporation of up to 5% cardiolipin into DMPC liposomes increased the rate of fusion more than 200-fold. The addition of adriamycin to cardiolipin-containing liposomes further enhanced the rate of the fusion. In contrast, liposomes containing other phospholipids, including phosphatidylglycerol, sphingomyelin, and phosphatidylserine, were not as sensitive to the addition of adriamycin. The largest increase in the rate of fusion was observed when calcium ions were also present with adriamycin. Cardiolipin-containing liposomes again showed the greatest sensitivity. Adriamycin did not increase the permeability of DMPC liposomes to the paramagnetic ion, Pr 3+, either in the presence or absence of Ca 2+. However, in contrast, Pr 3+ did gain access to the inside of cardiolipin-containing liposomes. Adriamycin decreased the rate of ascorbate permeation into the bilayer of dipalmitoylphosphatidylcholine (DPPC) liposomes and DPPC liposomes containing small amounts of phosphatidylglycerol or phosphatidylserine. Conversely, adriamycin stimulated the rate of ascorbate permeation of cardiolipin-containing DPPC liposomes. These results suggest that adriamycin can modulate membrane structure and function and act in a differential and specific way with membranes containing cardiolipin.