title: Characterization of the colloidal properties, in vitro antifungal activity, antileishmanial activity and toxicity in mice of a di-stigma-steryl-hemi-succinoyl-glycero-phosphocholine liposome-intercalated amphotericin B.
abstract: 1,2-Di-stigma-steryl-hemi-succinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Since amphotericin B (AmB) interacts with sterols, we postulated that DSHemsPC could be used in AmB liposome formulations. Thirty-two DSHemsPC-AmB formulations were prepared using various mole ratios of DSHemsPC, phosphatidylcholine and phosphatidylglycerol at different pH. Most formulations had physical properties similar to AmBisome™: a particle diameter of about 100 nm, a monomodal distribution and a negative zeta potential. The red blood cell potassium release (RBCPR) IC50s for formulations spanned a range, with some being comparable to or greater than the IC50 observed using AmBisome™. A number of formulations had superior in vitro antifungal activity compared to AmBisome™ against all of the tested pathogenic yeasts and molds. The IC50s of formulations against Leishmania major promastigotes and amastigotes for certain formulations were comparable with AmBisome™ and Fungizone™. Most formulations had maximum tolerated intravenous doses (MTD) of less than 10 mg/kg. However the formulation consisting of DSHemsPC/DMPC/DMPG/AmB mole ratio 1.25/5.0/1.5/1.0 (prepared at pH 5.5) had excellent colloidal properties, a high IC50 for RBCPR, antifungal and antileishmanial activity similar to AmBisome™ and an MTD of 60 mg/kg. The characteristics of this DSHemsPC/DMPC/DMPG/AmB formulation make it suitable for further investigation to treat AmB-responsive pathogens.
authors.affiliation: Nanotechnology Research Center, Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, P.O. Box 91775-1365, Mashhad, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Iman
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Huang
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
authors.forename: Mahmoud R
authors.initials: MR
authors.lastname: Jaafari
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D018929:Cell Culture Techniques; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D020128:Inhibitory Concentration 50; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000737:chemistry*; D011817:Rabbits; D013265:Stigmasterol / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C559993:1,2-distigmasterylhemisuccinoyl-glycero-3-phosphocholine; D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D010713:Phosphatidylcholines; D000666:Amphotericin B; D013265:Stigmasterol