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

作者：dos Reis Lage Leticia Martins; Barichello Jose Mario; Lage Daniela Pagliara; Costa Mendonca Debora Vasconcelos; Ravena Severino Carvalho Ana Maria; Rodrigues Marcella Rezende; Menezes Souza Daniel; Roatt Bruno Mendes; Alves Ricardo Jose; Pereira Tavares Carlos Alberto; Ferraz Coelho Eduardo Antonio; Duarte Mariana Costa

来源：Parasitology Research, 2016, 115(11): 4083-4095.

DOI：10.1007/s00436-016-5181-4

• 8-Hydroxyquinoline
• In vivo treatment
• Tegumentary leishmaniasis
• Polymericmicelle
• Toxicity
• Leishmania amazonensis

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-gamma, 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-gamma 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.

• 出版日期2016-11