title: Poloxamer 407 (Pluronic(®) F127)-based polymeric micelles for amphotericin B: In vitro biological activity, toxicity and in vivo therapeutic efficacy against murine tegumentary leishmaniasis.
abstract: In the present study, a Poloxamer 407-based amphotericin B (AmpB)-containing polymeric micelles system (AmpB/M) was employed in the treatment of Leishmania amazonensis-infected BALB/c mice. Initially, the in vitro antileishmanial activity (IC50 value) of AmpB/M and B-AmpB/M (empty micelles) against stationary promastigotes and amastigotes-like forms of the parasites was determined, and results were of 1.83 ± 0.4 and 22.1 ± 0.7 μM, respectively, for the promastigotes, and of 2.27 ± 0.5 and 33.98 ± 2.6 μM, respectively, for the amastigotes-like. The cytotoxic concentration (CC50) values of these products were also evaluated, and we found the results of 119.5 ± 9.6 and 134.7 ± 10.3 μM, respectively. With these values, the selectivity index (SI) was calculated and results were of 65.3 and 5.4, respectively, for the promastigotes, and of 59.3 and 3.96, respectively, for the amastigotes-like of the parasites. Free AmpB showed IC50 values of 1.2 ± 0.3 and 2.5 ± 0.5 μM for the promastigotes and amastigotes-like, respectively, whereas the CC50 value was of 9.5 ± 0.4 μM. The SI values of this drug were of 7.9 and 3.8, respectively, for the promastigote and amastigote-like stages of the parasites. After, animals were infected and received saline or were treated subcutaneously with free AmpB, AmpB/M or B-AmpB/M. In the results, free AmpB-treated and infected mice showed reductions in their body weight, which were associated with hepatic and renal damage; however, no organic alteration was observed in the AmpB/M-treated animals. In addition, these animals showed significant reductions in their lesion average size and in the parasite burden in all evaluated infected tissue and organs, when compared to the other groups; as well as significantly higher levels of antileishmanial IFN-γ, IL-12, GM-CSF and nitrite, which were associated with low production of IL-4, IL-10 and IgG1 isotype antibodies. In conclusion, this AmpB/M system could be considered as an alternative for future studies in the treatment of tegumentary leishmaniasis.
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Débora V C
authors.initials: DV
authors.lastname: Mendonça
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Letícia M R
authors.initials: LM
authors.lastname: Lage
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Lage
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Chávez-Fumagalli
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ludolf
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Roatt
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes-Souza
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: André A G
authors.initials: AA
authors.lastname: Faraco
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rachel O
authors.initials: RO
authors.lastname: Castilho
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Carlos A P
authors.initials: CA
authors.lastname: Tavares
authors.affiliation: Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil; Laboratório de Tecnologia Farmacêutica, Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas, Campus Capão do Leão, S/N, Pelotas, RS, Brazil.
authors.forename: José Mário
authors.initials: JM
authors.lastname: Barichello
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Duarte
authors.affiliation: Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. Electronic address: eduardoferrazcoelho@yahoo.com.br.
authors.forename: Eduardo A F
authors.initials: EA
authors.lastname: Coelho
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005079:Excipients; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008099:Liver / Q000469:parasitology; D008198:Lymph Nodes / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D020442:Poloxamer; D011108:Polymers; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000469:parasitology
chemical_list: D000981:Antiprotozoal Agents; D016207:Cytokines; D005079:Excipients; D007074:Immunoglobulin G; D008823:Micelles; D011108:Polymers; D020442:Poloxamer; D000666:Amphotericin B
keywords: Amphotericin B; Leishmania amazonensis; Poloxamer 407; Tegumentary leishmaniasis; Toxicity; Treatment