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Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Abstract:
Polymeric micelles may serve as nanoscopic, long-circulating carriers of hydrophobic drugs. In this study, we have researched the solubilization of amphotericin B (AmB), an antifungal drug, by micelles of poly(ethylene oxide)-block-poly(beta benzyl-L-aspartate) (PEO-PBLA), the properties of the AmB-loaded PEO-PBLA micelles and the resultant haemolytic activity of AmB. AmB loading takes place during self assembly of PEO-PBLA micelles, and this occurs through a dialysis procedure as an alkaline aqueous solution replaces the selective solvent for the polymer and the drug. In this way, AmB reaches levels of 57 to 141 microg/ml, corresponding to a loading efficiency of 27-30% (loaded AmB/initial amount of AmB). The molar ratio of AmB to PEO-PBLA is 0.40 to 1.0. Pictures by transmission electron microscopy reveal spherical AmB-loaded PEO-PBLA micelles with a mean diameter of 25.8+/-4.2 nm. AmB-loaded PEO-PBLA micelles are nonhaemolytic at an AmB level of 10 microg/ml as assessed by release of haemoglobin, measured by UV-Vis spectroscopy. AmB as Fungizone, its standard formulation, completely lyses red blood cells at a level of 3.0 microg/ml in 30 min. In contrast, there is no haemolysis at 5.5 h for AmB-loaded PEO-PBLA micelles at 3.0 microg/ml of AmB, indicating the gradual release of AmB from PEO-PBLA micelles. PEO-PBLA itself is nonhaemolytic even at a level of 0.70 mg/ml. Most amphiphiles, e.g. sodium deoxycholate, present in Fungizone, are haemolytic. Finally, AmB-loaded PEO-PBLA micelles can be freeze-dried and easily reconstituted in water. Afterwards, AmB is present in the intact PEO-PBLA micelles and remains nonhaemolytic.
Insights
Polymeric micelles effectively solubilize the antifungal drug amphotericin B (AmB), showing reduced haemolytic activity compared to standard formulations. These AmB-loaded micelles are stable, freeze-dried, and non-haemolytic, offering a promising drug delivery system.
Area of Science:
- Nanotechnology
- Polymer Chemistry
- Pharmacology
Background:
- Hydrophobic drugs like amphotericin B (AmB) require effective delivery systems.
- Polymeric micelles offer potential as nanocarriers for improved drug circulation and solubilization.
- Poly(ethylene oxide)-block-poly(beta benzyl-L-aspartate) (PEO-PBLA) is a candidate polymer for micelle formation.
Purpose of the Study:
- To investigate the solubilization of amphotericin B (AmB) using PEO-PBLA polymeric micelles.
- To characterize the properties of AmB-loaded PEO-PBLA micelles.
- To evaluate the haemolytic activity of AmB delivered via PEO-PBLA micelles.
Main Methods:
- AmB loading into PEO-PBLA micelles via a dialysis procedure.
- Characterization of micelle size and morphology using transmission electron microscopy.
- Assessment of haemolytic activity by measuring haemoglobin release via UV-Vis spectroscopy.
Main Results:
- Successful solubilization of AmB into PEO-PBLA micelles with loading efficiencies of 27-30%.
- Transmission electron microscopy revealed spherical micelles with a mean diameter of 25.8 ± 4.2 nm.
- AmB-loaded PEO-PBLA micelles demonstrated significantly reduced haemolytic activity compared to Fungizone, with no haemolysis observed at 3.0 μg/ml AmB after 5.5 hours.
Conclusions:
- PEO-PBLA micelles are effective carriers for amphotericin B, enhancing its solubility.
- The AmB-loaded PEO-PBLA micelles exhibit a favorable safety profile, being non-haemolytic at therapeutic concentrations.
- These micelles can be freeze-dried and reconstituted, indicating their potential for stable pharmaceutical formulations.