Interaction of amphotericin B with polymeric colloids - A spectroscopic study

The self-association of the amphiphilic antifungal agent amphotericin B (AmB) in water has been shown to depend on numerous parameters which produce spectroscopic changes and is directly related to modifications in AmB toxicity. We have taken advantage of these changes to study the interactions of AmB with two different polymeric materials: poly(epsilon-caprolactone) and poloxamer 188. Both materials are components of a recently developed AmB formulation based on polymeric nanospheres, which have demonstrated reduced acute toxicity in mice as compared with free AmB. Poly(epsilon-caprolactone) composes the core of nanospheres, and poloxamer 188 is the stabilizer used to coat the particles. AmB dispersions with poly(E-caprolactone) nanospheres led to dramatic spectral changes as compared with free AmB dispersions, indicating an extensive reduction of the aggregation state of AmB and an increase in the threshold of its aggregation. These changes seem to be due to the binding of the drug onto the nanosphere surface. In contrast, dispersions of AmB with poloxamer led to an increase of AmB aggregation as a function of poloxamer concentration due to the formation of mixed micelles. Modification of the ionic charge of AmB molecules during the preparation of nanospheres did not have a significant effect on AmB self-organization. However, interaction of AmB with high concentration of poloxamer containing a larger hydrophobic region (polypropylene oxide, PPO) changed this organization by reducing the number of AmB aggregates as compared to the effect of more hydrophilic poloxamers. These results suggest that ionic and/or hydrogen bond interactions only play a minor role and that predominantly hydrophobic forces drive the interaction between AmB and these compounds, Both types of association were easily dissociated upon dilution (AmB concentration < 5 mu g/ml), indicating that the interactions of AmB with both polymeric materials are relatively weak. This low affinity between the drug and these compounds has been shown by the fact that such interactions were only achieved with formulations of precise composition obtained with a particular preparative process such as a solvent displacement method. This process forced AmB monomers solubilized in organic solvent - on evaporation of this solvent - to bind to nanospheres or to associate with poloxamer micelles instead of self-aggregating in water. (C) 1998 Elsevier Science B.V. All rights reserved.