title: Miltefosine-loaded lipid nanoparticles: Improving miltefosine stability and reducing its hemolytic potential toward erythtocytes and its cytotoxic effect on macrophages.
abstract: The toxic effects of miltefosine on the epithelial cells of the gastrointestinal tract and its hemolytic action on erythrocytes have limited its use as an antileishmanial agent. As part of our search for new strategies to overcome the side effects of miltefosine during the treatment of leishmaniasis, we have developed stable miltefosine-loaded lipid nanoparticles in an attempt to reduce the toxic effects of the drug. We have evaluated lipid nanoparticles containing varying amounts of miltefosine and cholesterol, prepared by sonication, in terms of their physicochemical properties, preliminary stability, hemolytic potential toward erythrocytes, and cytotoxicity to macrophages and to promastigote and amastigote forms of Leishmania (L.) chagasi. Miltefosine loading into lipid nanoparticles was 100% for low drug concentrations (7.0 to 20.0mg/mL). Particle size decreased from 143nm (control) to between 43 and 69nm. From fluorescence studies, it was observed that the presence of miltefosine and cholesterol (below 103μM) promoted ordering effects in the phospholipid region of the nanoparticles. The formulation containing 15mg/mL miltefosine was stable for at least six months at 4°C and in simulated gastrointestinal fluids, and did not promote epithelial gastrointestinal irritability in Balb/C mice. When loaded into lipid nanoparticles, the hemolytic potential of miltefosine and its cytotoxicity to macrophages diminished, while its antiparasitic activity remained unaltered. The results suggested that miltefosine-loaded lipid nanoparticles may be promising for the treatment of leishmaniasis and might be suitable for oral and parenteral use.
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil.
authors: José Jardes
authors: JJ
authors: da Gama Bitencourt
authors: Department of Physics, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo.
authors: Wallance Moreira
authors: WM
authors: Pazin
authors: Department of Physics, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo. Electronic address: amandosi@ffclrp.usp.
authors: Amando Siuiti
authors: AS
authors: Ito
authors: Department of Physics, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo.
authors: Marina Berardi
authors: MB
authors: Barioni
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil.
authors: Carolline
authors: C
authors: de Paula Pinto
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil.
authors: Maria Aparecida Dos
authors: MA
authors: Santos
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil.
authors: Thales Henrique Santos
authors: TH
authors: Guimarães
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil.
authors: Márcia Regina Machado Dos
authors: MR
authors: Santos
authors: Department of Pharmacy and Biotechnology, Anhanguera, University of São Paulo (UNIAN-SP), Brazil. Electronic address: cvalduga@usp.br.
authors: Claudete Justina
authors: CJ
authors: Valduga
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004912:Erythrocytes / Q000187:drug effects; D005767:Gastrointestinal Diseases / Q000188:drug therapy / Q000473:pathology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000067996:RAW 264.7 Cells
chemical_list: D000981:Antiprotozoal Agents; D004337:Drug Carriers; D008055:Lipids; D010767:Phosphorylcholine; C039128:miltefosine
keywords: 6-NBD PC (1-palmitoyl-2-{6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl}-sn-glycero-3-phosphocholine) (CAS n(o) 91992-01-7); Hemolytic potential; Leishmaniasis; Lipid nanoparticles; Miltefosine; Miltefosine (PubChem CID: 3599); Tween 80 (PubChem CID: 6364656); cholesterol (PubChem CID: 5997); cotton-seed oil (PubChem SID: 135318054); glycerin (PubChem CID: 753); oleic acid (PubChem CID: 445639); phosphatidylcholine (PubChem CID: 45266626)