title: Liposomes versus lipid nanoparticles: comparative study of lipid-based systems as oryzalin carriers for the treatment of leishmaniasis.
abstract: Main-stay in treatment of leishmaniasis relies on chemotherapy but none of the current drugs combines high activity and low toxicity at affordable costs. Dinitroanilines are a new class of drugs with proved in vitro antileishmanial activity. However the development of their pharmaceutical formulations has been compromised by low water solubility and low accumulation in diseased organs. These limitations can be overcome by incorporation in lipid-based nanoformulations such as liposomes and solid lipid nanoparticles. In previous work this strategy was already followed with the incorporation of a dinitroaniline, oryzalin, resulting in the improvement of the biodistribution profile. The present work aims at demonstrating the in vitro and in vivo therapeutic activity of these oryzalin nanoformulations, and establishing a systematic comparison of both systems. After oryzalin incorporation suitable physicochemical properties for parenteral administration were obtained. Nanoformulations revealed reduced cytotoxicity and haemolytic activity when compared with free-oryzalin, while retaining the in vitro intracellular activity. Therapeutic activity, assessed in a murine model of visceral leishmaniasis, was evaluated in terms of number of administrations, dose-response and influence of the lipid excipient. Results demonstrate the superiority of both oryzalin nanoformulations on the reduction of parasitic burden in liver and spleen as compared to the control group (84 to 91%) and similar to Glucantime. A strong reduction in ED50 values (3 to 65 fold) as compared to free-oryzalin was also obtained, depending on the organ and nanoformulation used. Both oryzalin nanoformulations are potential candidates as therapeutic agents against visceral leishmaniasis.
authors.forename: R M
authors.initials: RM
authors.lastname: Lopes
authors.forename: M M
authors.initials: MM
authors.lastname: Gaspar
authors.forename: J
authors.initials: J
authors.lastname: Pereira
authors.forename: C V
authors.initials: CV
authors.lastname: Eleutério
authors.forename: M
authors.initials: M
authors.lastname: Carvalheiro
authors.forename: A J
authors.initials: AJ
authors.lastname: Almeida
authors.forename: M E M
authors.initials: ME
authors.lastname: Cruz
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry; D004058:Diffusion; D004136:Dinitrobenzenes / Q000008:administration & dosage* / Q000737:chemistry; D007891:Leishmania / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000473:pathology*; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D008422:Materials Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D013424:Sulfanilamides / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D004136:Dinitrobenzenes; D008055:Lipids; D008081:Liposomes; D053769:Nanocapsules; D013424:Sulfanilamides; C012465:oryzalin