title: Antifungal and immunomodulatory activity of a novel cochleate for amphotericin B delivery against Sporothrix schenckii.
abstract: BACKGROUND
  Sporotrichosis is an emergent subcutaneous mycoses caused by species of the Sporothrix schenckii complex. Amphotericin B (AmB) remains the main antifungal drug for the treatment of systemic infections, but its use is limited by toxicity reasons. AFCo3 is a novel cochleate containing detoxified LPS, which exhibits drug delivery and immunomodulating properties. Here, AFCo3 was used as the vehicle for AmB to evaluate the immunomodulatory and antifungal efficacy against S. schenckii in vitro and in vivo.
  
  
  RESULTS
  The minimum inhibitory concentrations of AFCo3-AmB and AmB were 0.25 and 1μg/mL respectively. The minimum fungicidal concentration was 0.5μg/mL for AFCo3-AmB and 2μg/mL for AmB. AFCo3-AmB was less cytotoxic than AmB for peritoneal macrophages, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and reduced the AmB-induced hemolysis in murine erythrocytes. AFCo3-AmB improved the intracellular killing of phagocytized yeast and it enhanced the in vitro production of IL-1β, TNF-α and NO in peritoneal macrophages. Moreover, AFCo3-AmB was more effective than AmB in reducing spleen and liver fungal burden after repeated (five days) intraperitoneal administration of 5mg/kg of AmB, in a Balb/c model of systemic infection, associated to a significant induction of Th1/Th17 response. Finally, blood chemistry revealed that AFCo3-AmB did not cause changes suggestive of nephrotoxicity, such as increases in total proteins, albumin, creatinine and blood urea nitrogen that were caused by free AmB.
  
  
  CONCLUSIONS
  AFCo3-AmB exhibited a significant immunomodulator action, reduced toxicity and improved antifungal action against S. schenckii, suggesting a potential use as AmB delivery for systemic sporotrichosis treatment.
authors.affiliation: Immunotoxicology Laboratory, Toxicology and Biomedicine Center (TOXIMED), Medical Science University, Autopista Nacional Km. 1 1/2, CP 90400 Santiago de Cuba, Cuba; Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista Julio Mesquita Filho, UNESP, Rodovia Araraquara-Jaú - Km 1, CEP: 14801-902, Araraquara, São Paulo, Brazil. Electronic address: batistaduhartea@gmail.com.
authors.forename: A
authors.initials: A
authors.lastname: Batista-Duharte
authors.affiliation: Immunology Department, Vice presidency of Researches, Finlay Institute, La Habana, Cuba.
authors.forename: M
authors.initials: M
authors.lastname: Lastre
authors.affiliation: Immunology Department, Vice presidency of Researches, Finlay Institute, La Habana, Cuba.
authors.forename: B
authors.initials: B
authors.lastname: Romeu
authors.affiliation: Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista Julio Mesquita Filho, UNESP, Rodovia Araraquara-Jaú - Km 1, CEP: 14801-902, Araraquara, São Paulo, Brazil.
authors.forename: D L
authors.initials: DL
authors.lastname: Portuondo
authors.affiliation: Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista Julio Mesquita Filho, UNESP, Rodovia Araraquara-Jaú - Km 1, CEP: 14801-902, Araraquara, São Paulo, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Téllez-Martínez
authors.affiliation: Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista Julio Mesquita Filho, UNESP, Rodovia Araraquara-Jaú - Km 1, CEP: 14801-902, Araraquara, São Paulo, Brazil.
authors.forename: F A
authors.initials: FA
authors.lastname: Manente
authors.affiliation: Immunology Department, Institute of Preclinical and Basic Sciences (ICBP) "Victoria de Girón", University of Medical Sciences of Havana, 146 No. 2504.e/ 25 Ave and 31 Ave, Playa, Havana, Cuba.
authors.forename: O
authors.initials: O
authors.lastname: Pérez
authors.affiliation: Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, Universidade Estadual Paulista Julio Mesquita Filho, UNESP, Rodovia Araraquara-Jaú - Km 1, CEP: 14801-902, Araraquara, São Paulo, Brazil. Electronic address: carlosiz@fcfar.unesp.br.
authors.forename: I Z
authors.initials: IZ
authors.lastname: Carlos
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009569:Nitric Oxide / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D013175:Sporothrix / Q000187:drug effects* / Q000254:growth & development; D013174:Sporotrichosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: C000618753:AFCo3 cochleate; D000935:Antifungal Agents; D016207:Cytokines; D004337:Drug Carriers; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D000666:Amphotericin B
keywords: Amphotericin B; Antifungal activity; Cochleates; Immunomodulation; Sporothrix schenckii; Sporotrichosis