Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG(5000)-b-PCL(x)) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy poly(ethylene glycol) (PEG-DSPE), possess small size and high thermodynamic stability, raising their potential as long circulating carriers in the context of delivery of antineoplastic and antibiotic drugs. Formation of mixed polymeric micelles was confirmed using size exclusion chromatography and 1H NMR NOESY. Steady-state fluorescence measurements revealed depressed critical micellar concentrations indicative of a cooperative interaction between component hydrophobic blocks, which was quantified using the pseudophase model for micellization. Steady-state fluorescence measurements indicated that the mixed polymeric micelle cores possess intermediate micropolarity and high microviscosity. Pulsed field gradient spin-echo measurements were used to characterize micellar diffusion coefficients, which agree well with those obtained using dynamic light scattering. NOE spectra suggested that the hydrophobic polymer segments from individual components are in close proximity, giving evidence for the formation of a relatively homogeneous core. Contrary to one-component PEG(5000)-b-PCL(x) micelles, the mixed polymeric micelles could incorporate clinically relevant levels of the poorly water soluble antibiotic, amphotericin B (AmB). AmB encapsulation and release studies revealed an interesting composition-dependent interaction of the drug with the mixed polymeric micelle core.

No abstract

Micelles formed from PEG-DSPE solubilize high levels of the poorly water-soluble antifungal amphotericin B (AmB). AmB release from PEG-DSPE micelles is slow in buffer but remarkably rapid in the presence of bovine serum albumin (BSA). Sequential changes in the absorbance spectrum of AmB in PEG-DSPE micelles point to a rapid dissociation of incorporated drug in the presence of BSA. In this context, we have studied micelles formed from PEG-DSPE which coincorporate cholesterol (PEG-DSPE|cholesterol). (1)H NMR measurements point to a lower mobility of lipid in PEG-DSPE|cholesterol micelles compared to PEG-DSPE micelles. The absorbance spectrum of AmB incorporated in PEG-DSPE|cholesterol micelles is distinct from that in PEG-DSPE micelles, which may point to differences in the drug-micelle interaction. AmB release from PEG-DSPE|cholesterol micelles is slow in buffer and in the presence of BSA. The absorption spectrum of AmB in PEG-DSPE|cholesterol micelles remained unchanged in BSA, further supporting stable incorporation and the slow release from the carrier.

These results indicate that AmB solubilized in PEG-DSPE micelles is compatible with solubilized rapamycin and 5-FC. The indifferent or moderately synergistic activity of combinations is encouraging and warrants further investigation in appropriate rodent models.