In vitro dissociation of antifungal efficacy and toxicity for amphotericinB-loaded poly(ethylene oxide)-block-poly( beta-benzyl-L-aspartate) micelles

Amphotericin B (AmB) is a membrane-active drug used frequently for the trea tment of systemic fungal diseases. Limitations for the use of AmB include p oor water solubility and potential for serious systemic toxicities. Recentl y, it has been demonstrated that the aggregation state of AmB is a determin ant factor for toxicity. To increase its therapeutic index, AmB has been so lubilized in micelles based on poly(ethylene oxide)-block-poly(beta-benzyl- L-aspartate) (PEO-block-PBLA), using a dialysis method of drug loading. The aggregation state of AmB has been investigated by electronic absorption sp ectroscopy. AmB loaded in PEO-block-PBLA micelles is non-hemolytic for conc entrations up to 15 mu g/ml. AmB as Fungizone(R) initiates hemolysis at 1.0 mu g/ml. The onset of hemolysis correlates with the respective critical ag gregation concentrations (CACs) of AmB. The antifungal activity of the AmB- loaded PEO-block-PBLA micelles is four to eight times higher than Fungizone (R) in terms of minimal inhibitory concentrations (MICs). PEO-block-PBLA ha s no antifungal activity for concentrations up to 200 mu g/ml. The basis fo r the increase in antifungal activity of AmB-loaded PEO-block-PBLA micelles is unclear, but may be related to a stabilizing effect of the polymeric mi celles against auto-oxidation of the AmB heptaene moiety or alternatively, an enhancement in membrane perturbation of fungal cells. (C) 1998 Elsevier Science B.V. All rights reserved.