title: Formulation of oryzalin (ORZ) liposomes: in vitro studies and in vivo fate.
abstract: Oryzalin (ORZ) is a dinitroaniline that has attracted increasing interest for the treatment of leishmaniasis. The possible use of ORZ as an antiparasitic agent is limited by low water solubility associated with an in vivo rapid clearance. The aim of this work was to overcome these unfavorable pharmaceutical limitations potentiating ORZ antileishmanial activity allowing a future clinical use. This was attained by incorporating ORZ in appropriate liposomes that act simultaneously as drug solvent and carrier delivering ORZ to the sites of Leishmania infection. The developed ORZ liposomal formulations efficiently incorporated and stabilised ORZ increasing its concentration in aqueous suspensions at least 150 times without the need of toxic solvents. The incorporation of ORZ in liposomes reduced the in vitro haemolytic activity and cytotoxicity observed for the free drug, while ORZ exhibits a stable association with liposomes during the first 24h after parenteral administration, significantly reducing ORZ blood clearance and elimination from the body. Simultaneously, an increased ORZ delivery was observed in the main organs of leishmanial infection with a 9-13-fold higher accumulation as compared to the free ORZ. These results support the idea that ORZ performance was strongly improved by the incorporation in liposomes. Moreover, ORZ liposomal formulations can be administrated in vivo in aqueous suspensions without the need of toxic solvents. It is expected an improvement in the therapeutic activity of liposomal ORZ that will be tested in future work.
authors: iMed.UL - Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors: Rui M
authors: RM
authors: Lopes
authors: M Luísa
authors: ML
authors: Corvo
authors: Carla V
authors: CV
authors: Eleutério
authors: Manuela C
authors: MC
authors: Carvalheiro
authors: Effie
authors: E
authors: Scoulica
authors: M Eugénia M
authors: ME
authors: Cruz
mesh_terms: D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004136:Dinitrobenzenes / Q000008:administration & dosage* / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D007896:Leishmaniasis / Q000188:drug therapy; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D012995:Solubility; D013424:Sulfanilamides / Q000008:administration & dosage* / Q000737:chemistry*; D013535:Suspensions / Q000008:administration & dosage / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004136:Dinitrobenzenes; D004337:Drug Carriers; D008081:Liposomes; D013424:Sulfanilamides; D013535:Suspensions; D014867:Water; C012465:oryzalin