ORIGINAL ARTICLE Lipid nanoparticles for amphotericin delivery in the treatment of American tegumentary leishmaniasis Regina Maia de Souza 1 & Raul Cavalcante Maranhão 2,3 & Elaine Rufo Tavares 2 & Fabíola Branco Filippin-Monteiro 4 & Antônio Carlos Nicodemo 1 & Aleksandra Tiemi Morikawa 2 & Edite Hatsumi Yamashiro Kanashiro 5 & Valdir Sabbaga Amato 1 # Controlled Release Society 2019 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. Keywords Leishmaniasis treatment . Lipid nanoparticles . Amphotericin . Cholesterol . Nanoemulsions Introduction Leishmania infections occur in the five continents and repre- sent a serious public health challenge. The World Health Organization estimates that 350 million people in 88 countries are at risk of contracting the disease and approximately two million new cases with variable clinical manifestations are reported annually. Of these, 1.5 million cases correspond to cutaneous leishmaniasis [1]. American tegumentary leishman- iasis (ATL) can be clinically manifested as cutaneous, diffuse cutaneous, and mucosal forms [2, 3]. Despite the great epide- miologic importance, leishmaniasis is considered a neglected disease in terms of pharmacological research, preventive ef- forts, and control initiatives [4–6]. In this respect, the current pharmacological weaponry against leishmaniasis is far from satisfactory. * Raul Cavalcante Maranhão ramarans@usp.br 1 Department of Infectious and Parasitic Diseases, School of Medicine, University of São Paulo, São Paulo, Brazil 2 Lipid Metabolism Laboratory, Heart Institute, Medical School Hospital, University of São Paulo, São Paulo, Brazil 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 4 Clinical Analysis Department, Faculty of Pharmaceutical Sciences, University of Santa Catarina, Florianópolis, Brazil 5 Laboratory of Seroepidemiology and Immunobiology, Tropical Medicine Institute, School of Medicine, University of São Paulo, São Paulo, Brazil Drug Delivery and Translational Research https://doi.org/10.1007/s13346-019-00677-4