title: Nanoscaled hydrated antimony (V) oxide as a new approach to first-line antileishmanial drugs.
abstract: BACKGROUND
  Coordination compounds of pentavalent antimony have been, and remain, the first-line drugs in leishmaniasis treatment for >70 years. Molecular forms of Sb (V) complexes are commercialized as sodium stibogluconate (Pentostam®) and meglumine antimoniate (MA) (Glucantime®). Ever-increasing drug resistance in the parasites limits the use of antimonials, due to the low drug concentrations being administered against high parasitic counts. Sb5+toxicity provokes severe side effects during treatment. To enhance therapeutic potency and to increase Sb (V) concentration within the target cells, we decided to try a new active substance form, a hydrosol of Sb2O5·nH2O nanoparticles (NPs), instead of molecular drugs.
  
  
  RESULTS
  Sb2O5·nH2O NPs were synthesized by controlled SbCl5hydrolysis in a great excess of water. Sb2O5·nH2O phase formation was confirmed by X-ray diffraction. The surface of Sb (V) NPs was treated with ligands with a high affinity for target cell membrane receptors. The mean particle size determined by dynamic light scattering and transmission electron microscopy was ~35-45 nm. In vitro tests demonstrated a 2.5-3 times higher antiparasitic activity of Sb (V) nanohybrid hydrosols, when compared to MA solution. A similar comparison for in vivo treatment of experimental cutaneous leishmaniasis with Sb5+nanohybrids showed a 1.75-1.85 times more effective decrease in the lesions. Microimages of tissue fragments confirmed the presence of NPs inside the cytoplasm of infected macrophages.
  
  
  CONCLUSIONS
  Sb2O5·nH2O hydrosols are proposed as a new form of treatment for cutaneous leishmaniasis caused byLeishmania amazonensis. The NPs penetrate directly into the affected cells, creating a high local concentration of the drug, a precondition to overcoming the parasite resistance to molecular forms of pentavalent antimonials. The nanohybrids are more effective at a lower dose, when compared to MA, the molecular drug. Our data suggest that the new form of treatment has the potential to reduce and simplify the course of cutaneous leishmaniasis treatment. At the same time, Sb2O5·nH2O hydrosols provide an opportunity to avoid toxic antimony (V) spreading throughout the body.
authors.affiliation: Laboratory of Leishmaniasis and Chagas Disease, National Institute of Amazonian Research (INPA), Manaus, Amazonas, Brazil.
authors.forename: Antonia Mr
authors.initials: AM
authors.lastname: Franco
authors.affiliation: Department of Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Iryna
authors.initials: I
authors.lastname: Grafova
authors.affiliation: Laboratory of Leishmaniasis and Chagas Disease, National Institute of Amazonian Research (INPA), Manaus, Amazonas, Brazil; Multi-Institutional Post-Graduate Program in Biotechnology, Federal University of Amazonas, Manaus, Amazonas, Brazil.
authors.forename: Fabiane V
authors.initials: FV
authors.lastname: Soares
authors.affiliation: Institute for Polymers, Composites, and Biomaterials, National Research Council, Pozzuoli, Naples Province, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Gentile
authors.affiliation: Laboratory of Leishmaniasis and Chagas Disease, National Institute of Amazonian Research (INPA), Manaus, Amazonas, Brazil; Multi-Institutional Post-Graduate Program in Biotechnology, Federal University of Amazonas, Manaus, Amazonas, Brazil.
authors.forename: Claudia Dc
authors.initials: CD
authors.lastname: Wyrepkowski
authors.affiliation: Laboratory of Environmental Chemistry, National Institute of Amazonian Research (INPA), Manaus, Amazonas, Brazil.
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Bolson
authors.affiliation: Laboratory of Environmental Chemistry, National Institute of Amazonian Research (INPA), Manaus, Amazonas, Brazil.
authors.forename: Ézio
authors.initials: É
authors.lastname: Sargentini
authors.affiliation: Institute for Polymers, Composites, and Biomaterials, National Research Council, Pozzuoli, Naples Province, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Carfagna
authors.affiliation: Department of Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Leskelä
authors.affiliation: Department of Chemistry, University of Helsinki, Helsinki, Finland.
authors.forename: Andriy
authors.initials: A
authors.lastname: Grafov
mesh_terms: D000818:Animals; D000965:Antimony / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000067493:Dynamic Light Scattering; D007894:Leishmania mexicana / Q000187:drug effects / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy; D008297:Male; D008647:Mesocricetus; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology*; D010316:Particle Size; D014961:X-Ray Diffraction
chemical_list: D000981:Antiprotozoal Agents; D010087:Oxides; C091696:antimony oxide; D000965:Antimony
keywords: TEM; hydrated antimony (V) oxide; leishmaniasis; nanoparticle; transmission electron microscopy