Amphotericin B (AmB), a poorly soluble and toxic antifungal drug, was encapsulated into polymeric
micelles self-assembled from
phenylboronic acid-functionalized
polycarbonate/PEG (PEG-PBC) and
urea-functionalized
polycarbonate/PEG (PEG-PUC) diblock copolymers via hydrogen-bonding, boronate
ester bond, and/or ionic interactions between the
boronic acid group in the micellar core and
amine group in AmB. Three micellar formulations were prepared: AmB/B
micelles using PEG-PBC, AmB/U
micelles using PEG-PUC and AmB/B+U mixed
micelles using 1:1molar ratio of PEG-PBC and PEG-PUC. The average particle sizes of the
micelles were in the range of 54.4-84.8nm with narrow size distribution and zeta potentials close to neutral. UV-Vis absorption analysis indicated that AmB/B
micelles significantly reduced AmB aggregation status due to the interactions between AmB and the micellar core, while Fungizone® and AmB/U
micelles had no effect. AmB/B+U mixed
micelles exerted an intermediate effect. Both AmB/B
micelles and AmB/B+U mixed
micelles showed sustained drug release, with 48.6±2.1% and 59.2±1.8% AmB released respectively after 24hunder sink conditions, while AmB/U
micelles displayed a burst release profile. All AmB-loaded
micelles showed comparable antifungal activity to free AmB or Fungizone®, while AmB/B
micelles and AmB/B+U mixed
micelles were much less hemolytic than other formulations. Histological examination showed that AmB/B and AmB/B+U
micelles led to a significantly lower number of apoptotic cells in the kidneys compared to Fungizone®, suggesting reduced nephrotoxicity of the micellar formulations in vivo. These
phenylboronic acid-functionalized polymeric
micelle systems are promising
drug carriers for AmB to reduce non-specific toxicities without compromise in antifungal activity.
STATEMENT OF SIGNIFICANCE: There is a pressing need for a novel and cost-effective delivery system to reduce the toxicity induced by the
antifungal agent,
amphotericin B (AmB). In this study,
phenylboronic acid-functionalized
polycarbonate/PEG diblock copolymers were used to fabricate
micelles for improved AmB-
micelle interaction via the manipulation of hydrogen-bonding, boronate
ester bond, ionic and hydrophobic interactions. Compared to free AmB and Fungizone®, the resultant micellar systems displayed improved stability while reducing non-specific toxicities without a compromise in antifungal activity. These findings demonstrate the potential of biodegradable functional
polycarbonate micellar systems as promising carriers of AmB for the treatment of systemic
fungal infections.