title: Posaconazole-Loaded Leukocytes as a Novel Treatment Strategy Targeting Invasive Pulmonary Aspergillosis.
abstract: Impaired delivery of antifungals to hyphae within necrotic lesions is thought to contribute to therapeutic failure in invasive pulmonary aspergillosis (IPA). We hypothesized that transfusion of leukocytes loaded ex vivo with the lipophilic antifungal posaconazole could improve delivery of antifungals to the sites of established infection and improve outcome in experimental IPA.
  
  
  
  The HL-60 leukemia cell line was differentiated to a neutrophil-like phenotype (differentiated HL-60 [dHL-60] cells) and then exposed to a range of posaconazole concentrations. The functional capacity and antifungal activity of these cells were assessed in vitro and in a mouse model of IPA.
  
  
  
  Posaconazole levels in dHL-60 cells were 265-fold greater than the exposure concentration. Posaconazole-loaded cells were viable and maintained their capacity to undergo active chemotaxis. Contact-dependent transfer of posaconazole from dHL-60 cells to hyphae was observed in vitro, resulting in decreased fungal viability. In a neutropenic mouse model of IPA, treatment with posaconazole-loaded dHL-60 cells resulted in significantly reduced fungal burden in comparison to treatment with dHL-60 cells alone.
  
  
  
  Posaconazole accumulates at high concentrations in dHL-60 cells and increases their antifungal activity in vitro and in vivo. These findings suggest that posaconazole-loading of leukocytes may hold promise for the therapy of IPA.
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Shane R
authors: SR
authors: Baistrocchi
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Mark J
authors: MJ
authors: Lee
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Melanie
authors: M
authors: Lehoux
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Benjamin
authors: B
authors: Ralph
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Brendan D
authors: BD
authors: Snarr
authors: Biochemistry Division, Hôpital Maisonneuve-Rosemont, CIUSSS Est-de-l'Île-de-Montréal, Montréal, Canada.
authors: Robert
authors: R
authors: Robitaille
authors: Department of Microbiology and Immunology, McGill University.|Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre.
authors: Donald C
authors: DC
authors: Sheppard
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole
keywords: Aspergillus fumigatus; HL-60; invasive pulmonary aspergillosis; neutrophil; posaconazole