title: NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency.
abstract: OBJECTIVE
  NanoDisk-amphotericin B (ND-AMB) is a protein-phospholipid bioparticle containing a "super aggregate" form of antifungal AMB. While lipid-based formulations of AMB, including liposomal AMB (L-AMB), are safer than the deoxycholate (DOC) solubilized form (DOC-AMB), the potency of lipid-based formulations is attenuated. We have developed an AMB-based therapy that is both well tolerated and fully efficacious.
  
  
  METHODS
  Potency was determined using broth culture growth-inhibition assays and candidacidal kinetics by quantitative culture plating. Toxicology studies were performed in healthy mice. Efficacy was assessed using both immune-competent and leukopenic murine models of systemic Candida albicans infection.
  
  
  RESULTS
  ND-AMB C. albicans and Aspergillus fumigatus minimum inhibitory concentrations were fourfold and sixfold lower, respectively, than that observed for L-AMB. ND-AMB exhibited candidacidal activity at 0.125 mg/L, 16-fold lower than L-AMB. In mice, ND-AMB produced no statistically significant kidney or liver toxicity at 15 mg/kg, the highest dose tested. When evaluated in immune-competent mice infected with C. albicans, ND-AMB was at least as effective as DOC-AMB or L-AMB. In a leukopenic model of candidiasis, the 50% effective dose of ND-AMB was around threefold lower than L-AMB.
  
  
  CONCLUSIONS
  These results indicate that ND-AMB exhibits a more favorable safety profile while maintaining uncompromised antifungal properties compared to both DOC-AMB and L-AMB. ND-AMB is a promising therapy for the treatment of invasive fungal infections.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA ; Lypro Biosciences, Berkeley, CA, USA.
authors.forename: Braydon L
authors.initials: BL
authors.lastname: Burgess
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: He
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA ; Lypro Biosciences, Berkeley, CA, USA.
authors.forename: Mandie M
authors.initials: MM
authors.lastname: Baker
authors.affiliation: Lypro Biosciences, Berkeley, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Luo
authors.affiliation: Lypro Biosciences, Berkeley, CA, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Carroll
authors.affiliation: Lypro Biosciences, Berkeley, CA, USA.
authors.forename: Trudy M
authors.initials: TM
authors.lastname: Forte
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
mesh_terms: D000666:Amphotericin B / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002176:Candida albicans; D002177:Candidiasis / Q000188:drug therapy / Q000401:mortality; D005260:Female; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D049329:Nanostructures / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D018675:Toxicity Tests
chemical_list: D000935:Antifungal Agents; D000666:Amphotericin B
keywords: apolipoprotein A-I; candidiasis; drug delivery; infectious diseases; nanoparticles