title: Leishmanicidal activity of amphotericin B encapsulated in PLGA-DMSA nanoparticles to treat cutaneous leishmaniasis in C57BL/6 mice.
abstract: The major goal of this work was to design a new nanoparticle drug delivery system for desoxycholate amphotericin B (D-AMB), based on controlled particle size, looking for the most successful release of the active agents in order to achieve the best site-specific action of the drug at the therapeutically optimal rate and dose regimen. For this, AMB nanoencapsulated in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles (Nano-D-AMB) has been developed, and its efficacy was evaluated in the treatment of experimental cutaneous leishmaniasis in C57BL/6 mice, to test if our nano-drug delivery system could favor the reduction of the dose frequency required to achieve the same therapeutic level of free D-AMB, and so, an extended dosing interval. Magnetic citrate-coated maghemite nanoparticles were added to this nanosystem (Nano-D-AMB-MG) aiming to increase controlled release of AMB by magnetohyperthermia. Female mice (N=6/group) were infected intradermally in the right footpad with promastigotes of Leishmania amazonensis in the metacyclic phase, receiving the following intraperitoneal treatments: 1% PBS for 10 consecutive days; D-AMB at 2 mg/kg/day for 10 days (totalizing 20 mg/kg/animal); Nano-D-AMB and Nano-D-AMB-MG at 6 mg/kg on the 1st, 4th and 7th days and at 2 mg/kg on the 10th day, also totalizing 20 mg/kg/animal by treatment end. The Nano-D-AMB-MG group was submitted to an AC magnetic field, allowing the induction of magnetohyperthermia. The evaluations were through paw diameter measurements; parasite number and cell viability were investigated by limiting dilution assay. D-AMB-coated PLGA-DMSA nanoparticles showed the same efficacy as free D-AMB to reduce paw diameter; however, the Nano-D-AMB treatment also promoted a significantly greater reduction in parasite number and cell viability compared with free D-AMB. The nano-drug AMB delivery system appeared more effective than free D-AMB therapy to reduce the dose frequency required to achieve the same therapeutic level. It thus favors a longer interval between doses, as expected with development of a new nano drug delivery system, and may be useful in the treatment of many different pathologies, from cancer to neurodegenerative diseases.
authors.affiliation: Faculdade de Ciências da Saúde, Laboratório de Dermatomicologia, Universidade de Brasília, 70910-900 Brasília, Brazil.
authors.forename: Ricardo Fontoura
authors.initials: RF
authors.lastname: de Carvalho
authors.forename: Ieler Ferreira
authors.initials: IF
authors.lastname: Ribeiro
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Miranda-Vilela
authors.forename: José
authors.initials: J
authors.lastname: de Souza Filho
authors.forename: Olímpia Paschoal
authors.initials: OP
authors.lastname: Martins
authors.forename: Débora de Oliveira
authors.initials: Dde O
authors.lastname: Cintra e Silva
authors.forename: Antônio Cláudio
authors.initials: AC
authors.lastname: Tedesco
authors.forename: Zulmira Guerrero Marques
authors.initials: ZG
authors.lastname: Lacava
authors.forename: Sônia Nair
authors.initials: SN
authors.lastname: Báo
authors.forename: Raimunda Nonata Ribeiro
authors.initials: RN
authors.lastname: Sampaio
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D016503:Drug Delivery Systems; D004355:Drug Stability; D005260:Female; D019344:Lactic Acid; D007894:Leishmania mexicana; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000648:ultrastructure; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D004113:Succimer
chemical_list: D000981:Antiprotozoal Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000666:Amphotericin B; D004113:Succimer
keywords: Cutaneous leishmaniasis; Desoxycholate amphotericin B; Nanobiotechnology