title: Topical amphotericin B in ultradeformable liposomes: Formulation, skin penetration study, antifungal and antileishmanial activity in vitro.
abstract: Aiming to improve the topical delivery of AmB to treat cutaneous fungal infections and leishmaniasis, ultradeformable liposomes containing amphotericin B (AmB-UDL) were prepared, and structural and functional characterized. The effect of different edge activators, phospholipid and AmB concentration, and phospholipid to edge activator ratio on liposomal deformability, as well as on AmB liposomal content, was tested. Liposomes having Tween 80 as edge activator resulted of maximal deformability and AmB/phospholipid ratio. These consisted of AmB-UDL of 107±8nm diameter, 0.078-polydispersity index and -3±0.2mV Z potential, exhibiting monomeric AmB encapsulated in the bilayer at a 75% encapsulation efficiency. After its cytotoxicity on keratinocytes (HaCaT cells) and macrophages (J774 cells) was determined, the in vitro antifungal activity of AmB-UDL was assayed. It was found that fungal strains (albicans and non-albicans Candida ATCC strains and clinical isolates of C. albicans) were more sensitive to AmB-UDL than mammal cells. Minimum inhibitory concentration values for AmB-UDL were 5-24 and 24-50 times lower than IC50 for J774 and HaCaT cells, respectively. AmB-UDL at 1.25μg/ml also displayed 100 and 75% anti- Leishmania braziliensis promastigote and amastigote activity, respectively. Finally, upon 1h of non-occlusive incubation, the total accumulation of AmB in human skin was 40 times higher when applied as AmB-UDL than as AmBisome. AmB-UDL provided a profound AmB penetration toward deep epithelial layers, achieved without classical permeation enhancers. Because of that, topical treatments of cutaneous fungal infection and leishmaniasis with AmB-UDL may be regarded of potential of clinical significance.
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Perez
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina.
authors.forename: Maria Julia
authors.initials: MJ
authors.lastname: Altube
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina.
authors.forename: Priscila
authors.initials: P
authors.lastname: Schilrreff
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Apezteguia
authors.affiliation: Centro de Pesquisas Gonçalo Muniz, CPQGM-FIOCRUZ, Brazil.
authors.forename: Fabiana Santana
authors.initials: FS
authors.lastname: Celes
authors.affiliation: Farmacognosia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Suipacha 531, Rosario 2000, Santa Fe, Argentina.
authors.forename: Susana
authors.initials: S
authors.lastname: Zacchino
authors.affiliation: Centro de Pesquisas Gonçalo Muniz, CPQGM-FIOCRUZ, Brazil.
authors.forename: Camila Indiani
authors.initials: CI
authors.lastname: de Oliveira
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina.
authors.forename: Eder Lilia
authors.initials: EL
authors.lastname: Romero
authors.affiliation: Nanomedicine Research Program, Departamento de Ciencia y Tecnologia, Universidad Nacional de Quilmes, Roque Saenz Peña 352, Bernal B1876 BXD, Buenos Aires, Argentina. Electronic address: jmorilla@unq.edu.ar.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Morilla
mesh_terms: D000666:Amphotericin B / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004339:Drug Compounding; D006801:Humans; D020128:Inhibitory Concentration 50; D015603:Keratinocytes / Q000187:drug effects / Q000382:microbiology / Q000469:parasitology; D007892:Leishmania braziliensis / Q000187:drug effects / Q000254:growth & development; D008081:Liposomes / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology / Q000469:parasitology; D051379:Mice; D008826:Microbial Sensitivity Tests; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry; D012867:Skin / Q000187:drug effects / Q000382:microbiology / Q000469:parasitology; D012869:Skin Absorption; D055672:Static Electricity
chemical_list: D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D008081:Liposomes; D011136:Polysorbates; C068538:liposomal amphotericin B; D000666:Amphotericin B
keywords: Candida spp.; Flexible liposomes; Leishmania braziliensis; Nanomedicine; Skin delivery