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An 8-hydroxyquinoline-containing polymeric micelle system is effective for the treatment of murine tegumentary leishmaniasis

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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.

Therapeutic scheme and immunological and parasitological parameters developed in the present study

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Acknowledgments

This work was supported by grants from Instituto Nacional de Ciência e Tecnologia em Nano-biofarmacêutica (INCT-NanoBiofar), FAPEMIG (CBB-APQ-00819-12 and CBB-APQ-01778-2014), and CNPq (APQ-482976/2012-8, APQ-488237/2013-0, and APQ-467640/2014-9). EAFC is a grant recipient of CNPq.

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Authors and Affiliations

  1. Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil

    Letícia Martins dos Reis Lage, Ana Maria Ravena Severino Carvalho, Marcella Rezende Rodrigues, Daniel Menezes-Souza, Bruno Mendes Roatt, Eduardo Antonio Ferraz Coelho & Mariana Costa Duarte

  2. Departamento de Farmácia, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, 35400-000, Minas Gerais, Brazil

    José Mário Barichello

  3. 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

    José Mário Barichello

  4. 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

    Daniela Pagliara Lage, Débora Vasconcelos Costa Mendonça, Daniel Menezes-Souza, Eduardo Antonio Ferraz Coelho & Mariana Costa Duarte

  5. Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil

    Ricardo José Alves

  6. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Minas Gerais, Brazil

    Carlos Alberto Pereira Tavares

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  1. Letícia Martins dos Reis Lage
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  2. José Mário Barichello
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  11. Eduardo Antonio Ferraz Coelho
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Correspondence to Eduardo Antonio Ferraz Coelho.

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Highlights

⇒ An 8-hydroxyquinoline-containing micelles system (8-HQN/M) was prepared. ⇒ This composition was effective against L. amazonensis in in vitro assays. ⇒ No toxicity was observed in murine macrophages and human red cells. ⇒ L. amazonensis-infected BALB/c mice were treated with 8-HQN/M. ⇒ They showed reduction in the lesion size and parasite load. ⇒ A Th1 immune response was developed in the 8-HQN/M-treated and infected animals.

José Mário Barichello, Eduardo Antonio Ferraz Coelho, and Mariana Costa Duarte are co-senior authors.

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Lage, L.M.d.R., Barichello, J.M., Lage, D.P. et al. An 8-hydroxyquinoline-containing polymeric micelle system is effective for the treatment of murine tegumentary leishmaniasis. Parasitol Res 115, 4083–4095 (2016). https://doi.org/10.1007/s00436-016-5181-4

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