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Lipid nanoparticles for amphotericin delivery in the treatment of American tegumentary leishmaniasis

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Abstract

Leishmaniasis occurs in the five continents and represents a serious public health challenge, but is still a neglected disease, and the current pharmacological weaponry is far from satisfactory. Triglyceride-rich nanoparticles mimicking chylomicrons (TGNP) behave metabolically like native chylomicrons when injected into the bloodstream. Previously we have shown that TGNP as vehicle to amphothericin B (AB) for treatment of fungi infection showed reduced renal toxicity and lower animal death rates compared to conventional AB. The aim of the current study was to test the tolerability and effectiveness of the TGNP-AB preparation in a murine model of Leishmania amazonensis infection. The in vitro assays determined the cytotoxicity of TGNP-AB, AB, and TGNP in macrophages and promastigote forms and the leishmanicidal activity in infected macrophages. The in vivo toxicity tests were performed in healthy mice with increasing doses of TGPN-AB and AB. Then, animals were treated with 2.5 mg/kg/day of AB, 17.5 mg/kg/day of TGNP-AB, or TGNP three times a week for 4 weeks. TGNP-AB formulation was less cytotoxic for macrophages than AB. TGNP-AB was more effective than AB against the promastigotes forms of the parasite and more effective in reducing the number of infected macrophages and the number of amastigotes forms per cell. TGNP-AB-treated animals showed lower hepatotoxicity. In addition, TGNP-AB group showed a marked reduction in lesion size on the paws and parasitic load. The TGNP-AB preparation attained excellent leishmanicidal activity with remarkable lower drug toxicity at very high doses that, due to the toxicity-buffering properties of the nanocarrier, become fully tolerable.

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Funding

This work was supported by National Council for Scientific and Technological Development (CNPq, Brazil-479291/2012-8), the São Paulo Research Foundation (FAPESP, Brazil-2015/10038-0), and National Institute of Science and Technology-Complex Fluids (INCT-FCx, Brazil).

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Authors and Affiliations

  1. Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paulo, Brazil

    Regina Maia de Souza, Antônio Carlos Nicodemo & Valdir Sabbaga Amato

  2. Lipid Metabolism Laboratory, Heart Institute, Medical School Hospital, University of São Paulo, São Paulo, Brazil

    Raul Cavalcante Maranhão, Elaine Rufo Tavares & Aleksandra Tiemi Morikawa

  3. Laboratório de Metabolismo e Lípides, Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), Av. Dr. Enéas de Carvalho Aguiar, 44, bloco 2, 1° subsolo, São Paulo, SP, Brazil

    Raul Cavalcante Maranhão

  4. Clinical Analysis Department, Faculty of Pharmaceutical Sciences, University of Santa Catarina, Florianópolis, Brazil

    Fabíola Branco Filippin-Monteiro

  5. Laboratory of Seroepidemiology and Immunobiology, Tropical Medicine Institute, School of Medicine, University of São Paulo, São Paulo, Brazil

    Edite Hatsumi Yamashiro Kanashiro

Authors
  1. Regina Maia de Souza
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  2. Raul Cavalcante Maranhão
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  3. Elaine Rufo Tavares
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  5. Antônio Carlos Nicodemo
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  7. Edite Hatsumi Yamashiro Kanashiro
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  8. Valdir Sabbaga Amato
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Correspondence to Raul Cavalcante Maranhão.

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All institutional and national guidelines for the care and use of laboratory animals were followed. This study is in agreement with the Guide for the Care and Use of Laboratory Animals of the Brazilian National Council of Animal Experimentation (CONCEA).

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de Souza, R.M., Maranhão, R.C., Tavares, E.R. et al. Lipid nanoparticles for amphotericin delivery in the treatment of American tegumentary leishmaniasis. Drug Deliv. and Transl. Res. 10, 403–412 (2020). https://doi.org/10.1007/s13346-019-00677-4

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