title: An 8-hydroxyquinoline-containing polymeric micelle system is effective for the treatment of murine tegumentary leishmaniasis.
abstract: The current treatment of leishmaniasis has been hampered due to the high toxicity of the available drugs and long duration protocols, which often lead to its abandonment. In the present study, a poloxamer 407-based delivery system was developed, and a molecule, 8-hydroxyquinoline (8-HQN), was incorporated with it, leading to an 8-HQN/micelle (8-HQN/M) composition. Assays were performed to evaluate the in vitro antileishmanial activity of 8-HQN/M against Leishmania amazonensis stationary promastigotes. The cytotoxicity in murine macrophages and in human red cells, as well as the efficacy of the treatment in macrophages infected by parasites, was also assessed. This product was also evaluated for the treatment of murine tegumentary leishmaniasis, using L. amazonensis-infected BALB/c mice. To evaluate the in vivo efficacy of the treatment, the average lesion diameter (area) in the infected tissue, as well as the parasite load at the site of infection (skin), spleen, liver and draining lymph nodes were examined. Non-incorporated micelle (B-8-HQN/M) and the free molecule (8-HQN) were used as controls, besides animals that received only saline. The parasite burden was evaluated by limiting dilution and quantitative real-time PCR (qPCR) techniques, and immunological parameters associated with the treatments were also investigated. In the results, the 8-HQN/M group, when compared to the others, presented more significant reductions in the average lesion diameter and in the parasite burden in the skin and all evaluated organs. These animals also showed significantly higher levels of parasite-specific IFN-γ, IL-12, and GM-CSF, associated with low levels of IL-4 and IL-10, when compared to the saline, 8-HQN/M, and B-8-HQN groups. A predominant IL-12-driven IFN-γ production, against parasite proteins, mainly produced by CD4+T cells, was observed in the treated animals, post-infection. In conclusion, 8-HQN/M was highly effective in treating L. amazonensis-infected BALB/c mice and can be considered alone, or combined with other drugs, as an alternative treatment for tegumentary leishmaniasis. Graphical Abstract Therapeutic scheme and immunological and parasitological parameters developed in the present study.
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Letícia Martins Dos Reis
authors.initials: LM
authors.lastname: Lage
authors.affiliation: Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, 35400-000, 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, 96900-010, 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, 30130-100, Minas Gerais, Brazil.
authors.forename: Daniela Pagliara
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, 30130-100, Minas Gerais, Brazil.
authors.forename: Débora Vasconcelos Costa
authors.initials: DV
authors.lastname: Mendonça
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Ana Maria Ravena Severino
authors.initials: AM
authors.lastname: Carvalho
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Marcella Rezende
authors.initials: MR
authors.lastname: Rodrigues
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.|Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Menezes-Souza
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Bruno Mendes
authors.initials: BM
authors.lastname: Roatt
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Alves
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.
authors.forename: Carlos Alberto Pereira
authors.initials: CA
authors.lastname: Tavares
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil. eduardoferrazcoelho@yahoo.com.br.|Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil. eduardoferrazcoelho@yahoo.com.br.
authors.forename: Eduardo Antonio Ferraz
authors.initials: EA
authors.lastname: Coelho
authors.affiliation: Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil.|Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Minas Gerais, Brazil.
authors.forename: Mariana Costa
authors.initials: MC
authors.lastname: Duarte
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D006801:Humans; D007894:Leishmania mexicana / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D015125:Oxyquinoline / Q000008:administration & dosage / Q000627:therapeutic use*; D059208:Parasite Load; D011108:Polymers; D013154:Spleen / Q000469:parasitology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D008823:Micelles; D011108:Polymers; D015125:Oxyquinoline
keywords: 8-Hydroxyquinoline; In vivo treatment; Leishmania amazonensis; Polymeric micelle; Tegumentary leishmaniasis; Toxicity