title: Nanoparticle formulations of decoquinate increase antimalarial efficacy against liver stage Plasmodium infections in mice.
abstract: Decoquinate has potent activity against both Plasmodium hepatic development and red cell replication when tested in vitro. Decoquinate, however, is practically insoluble in water. To achieve its maximal in vivo efficacy, we generated nanoparticle formulations of decoquinate with a mean particle size less than 400 nm. Three separate preparations at doses of decoquinate 0.5-5 mg/kg were examined in mice infected with Plasmodium berghei. Oral administration of nanoparticle decoquinate at a dose of 1.25 mg/kg effectively inhibited the liver-stage parasite growth and provided complete causal prophylactic protection. This efficacy is 15 fold greater than that observed for microparticle decoquinate, which requires minimal dose of 20 mg/kg for the same inhibitory effect. Further in vitro studies utilizing dose-response assays revealed that decoquinate nanoformulation was substantially more potent than decoquinate microsuspension in killing both liver and blood stage malarial parasites, proving its potential for therapeutic development.
  
  
  BACKGROUND
  In this study, a nanoparticle formulation of decoquinate is shown to have superior bioavailability and efficacy in a mouse model of malaria, paving the way to the development of novel, potentially less toxic and more effective therapeutics to combat a disease that still has an enormous impact on a global scale despite the available partially effective therapies.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA. Electronic address: henry.h.wang.ctr@us.army.mil.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Roncal
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry; D003667:Decoquinate / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010962:Plasmodium berghei / Q000187:drug effects
chemical_list: D000962:Antimalarials; D003667:Decoquinate
keywords: Causal prophylaxis; Malarial life cycle; Parasite growth; Particle size; Real time imaging