title: Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis.
abstract: Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections.
  
  
  BACKGROUND
  Aspergillus is an opportunistic pathogen, which affects immunocompromised patients. One novel way to help fight against this infection is pre-exposure prophylaxis. The authors here made PMA based anionic hydrogels carrying amphotericin B, with mucoadhesive behavior. They showed that aerosol route of the drug was very effective in protecting against the disease in an in-vivo model and should provide a stepping-stone towards clinical trials in the future.
authors: Departments of Medicine, Infectious Diseases, Immunity and Chemistry, Imperial College London, Hammersmith campus, London, UK.
authors: Khojasteh
authors: K
authors: Shirkhani
authors: Departments of Medicine, Infectious Diseases, Immunity and Chemistry, Imperial College London, Hammersmith campus, London, UK.
authors: Ian
authors: I
authors: Teo
authors: Departments of Medicine, Infectious Diseases, Immunity and Chemistry, Imperial College London, Hammersmith campus, London, UK.
authors: Darius
authors: D
authors: Armstrong-James
authors: Departments of Medicine, Infectious Diseases, Immunity and Chemistry, Imperial College London, Hammersmith campus, London, UK. Electronic address: s.shaunak@imperial.ac.uk.
authors: Sunil
authors: S
authors: Shaunak
mesh_terms: D000280:Administration, Inhalation; D000666:Amphotericin B / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects*; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D009330:Nebulizers and Vaporizers; D011109:Polymethacrylic Acids / Q000737:chemistry*; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000935:Antifungal Agents; D011109:Polymethacrylic Acids; D014409:Tumor Necrosis Factor-alpha; C030613:polymethacrylic acid; D000666:Amphotericin B; D007371:Interferon-gamma
keywords: Amphotericin B; Aspergillus fumigatus; Nebulised nanoparticle; Polymethacrylic acid; TNF-α and Interferon-γ