title: Polymeric micelles for drug delivery: solubilization and haemolytic activity of amphotericin B.
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.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: B G
authors.initials: BG
authors.lastname: Yu
authors.forename: T
authors.initials: T
authors.lastname: Okano
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.forename: G
authors.initials: G
authors.lastname: Kwon
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers; D005079:Excipients; D006461:Hemolysis / Q000187:drug effects*; D008823:Micelles; D008854:Microscopy, Electron; D010455:Peptides; D011092:Polyethylene Glycols; D011108:Polymers; D012995:Solubility
chemical_list: D000935:Antifungal Agents; D004337:Drug Carriers; D005079:Excipients; D008823:Micelles; D010455:Peptides; D011108:Polymers; C094116:poly(ethylene oxide-co-beta-benzyl-L-aspartate); D011092:Polyethylene Glycols; D000666:Amphotericin B