title: A phospholipid-apolipoprotein A-I nanoparticle containing amphotericin B as a drug delivery platform with cell membrane protective properties.
abstract: Amphotericin B (AMB), a potent antifungal agent, has been employed as an inhalable therapy for pulmonary fungal infections. We recently described a novel nano-sized delivery vehicle composed of phospholipid (PL) and apolipoprotein A-I, NanoDisk (ND), to which we added AMB as a payload (ND-AMB). The goal of the present study was to evaluate whether ND-AMB, compared to other formulations, preserves lung cell integrity in vitro, as AMB can be toxic to mammalian cells and reduce lung function when inhaled. Epithelial integrity was assessed by measuring K(+) ion flux across a model airway epithelium, Calu-3 cells. In this assay ND-AMB was at least 8-fold less disruptive than AMB/deoxycholate (DOC). Cell viability studies confirmed this observation. Unexpectedly, the ND vehicle restored the integrity of a membrane compromised by prior exposure to AMB. An alternative formulation of ND-AMB containing a high load of AMB per ND was not protective, suggesting that ND with a low ratio of AMB to PL can sequester additional AMB from membranes. ND-AMB also protected HepG2 cells from the cytotoxicity of AMB, as determined by cellular viability and lactate dehydrogenase (LDH) levels. This study suggests that ND-AMB may be safe for administration via inhalation and reveals a unique activity whereby ND-AMB protects lung epithelial membranes from AMB toxicity.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Braydon L
authors.initials: BL
authors.lastname: Burgess
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cavigiolio
authors.forename: Michelle V
authors.initials: MV
authors.lastname: Fannucchi
authors.forename: Beate
authors.initials: B
authors.lastname: Illek
authors.forename: Trudy M
authors.initials: TM
authors.lastname: Forte
authors.forename: Michael N
authors.initials: MN
authors.lastname: Oda
mesh_terms: D000280:Administration, Inhalation; D000666:Amphotericin B / Q000008:administration & dosage* / Q000009:adverse effects; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016632:Apolipoprotein A-I / Q000737:chemistry*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D016632:Apolipoprotein A-I; D004337:Drug Carriers; D010743:Phospholipids; D000666:Amphotericin B