title: Albumin-bound nanoparticles of practically water-insoluble antimalarial lead greatly enhance its efficacy.
abstract: We recently showed that the indolone-N-oxides can be promising candidates for the treatment of chloroquine-resistant malaria. However, the in vivo assays have been hampered by the very poor aqueous solubility of these compounds resulting in poor and variable activity. Here, we describe the preparation, characterization and in vivo evaluation of biodegradable albumin-bound indolone-N-oxide nanoparticles. Nanoparticles were prepared by precipitation followed by high-pressure homogenization and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The process was optimized to yield nanoparticles of controllable diameter with narrow size distribution suitable for intravenous administration, which guarantees direct drug contact with parasitized erythrocytes. Stable nanoparticles showed greatly enhanced dissolution rate (complete drug release within 30 min compared to 1.5% of pure drug) preserving the rapid antimalarial activity. The formulation achieved complete cure of Plasmodium berghei-infected mice at 25mg/kg with parasitemia inhibition (99.1%) comparable to that of artesunate and chloroquine and was remarkably more effective in prolonging survival time and inhibiting recrudescence. In 'humanized' mice infected with Plasmodium falciparum, the same dose proved to be highly effective: with parasitemia reduced by 97.5% and the mean survival time prolonged. This formulation can help advance the preclinical trials of indolone-N-oxides. Albumin-bound nanoparticles represent a new strategic approach to use this most abundant plasma protein to target malaria-infected erythrocytes.
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire de pharmacochimie et pharmacologie pour le développement, Pharma-DEV), F-31062 Toulouse cedex 9, France; IRD, UMR 152, F-31062 Toulouse cedex 9, France.
authors.forename: Nehal
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire de pharmacochimie et pharmacologie pour le développement, Pharma-DEV), F-31062 Toulouse cedex 9, France; IRD, UMR 152, F-31062 Toulouse cedex 9, France. Electronic address: hanygamal85@hotmail.com.
authors.forename: Hany
authors.initials: H
authors.lastname: Ibrahim
authors.affiliation: Unité de Parasitologie, Institut de Recherche Biomédicale des Armées (IRBA), Le Pharo, 13262 Marseille, France; Unité de Recherche Maladies Infectieuses et Tropicales Emergentes (URMITE), Faculté de Médecine La Timone, Université Aix-Marseille, 13385 Marseille cedex 5, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Dormoi
authors.affiliation: Unité de Parasitologie, Institut de Recherche Biomédicale des Armées (IRBA), Le Pharo, 13262 Marseille, France; Unité de Recherche Maladies Infectieuses et Tropicales Emergentes (URMITE), Faculté de Médecine La Timone, Université Aix-Marseille, 13385 Marseille cedex 5, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Briolant
authors.affiliation: Unité de Parasitologie, Institut de Recherche Biomédicale des Armées (IRBA), Le Pharo, 13262 Marseille, France; Unité de Recherche Maladies Infectieuses et Tropicales Emergentes (URMITE), Faculté de Médecine La Timone, Université Aix-Marseille, 13385 Marseille cedex 5, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.affiliation: Université Pierre et Marie Curie-Paris 6, UMR S945, Paris, France; Institut National de la Santé et de la Recherche Médicale, U945, Paris, France.
authors.forename: Alicia
authors.initials: A
authors.lastname: Moreno
authors.affiliation: Université Pierre et Marie Curie-Paris 6, UMR S945, Paris, France; Institut National de la Santé et de la Recherche Médicale, U945, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service Parasitologie-Mycologie, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.affiliation: Institut Charles-Gerhardt, UMR 5253 CNRS/UM2/ENSCM/UM1, 8 rue de l'école Normale, 34296 Montpellier cedex 05, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Legrand
authors.affiliation: Université de Toulouse, UPS, UMR 152 (Laboratoire de pharmacochimie et pharmacologie pour le développement, Pharma-DEV), F-31062 Toulouse cedex 9, France; IRD, UMR 152, F-31062 Toulouse cedex 9, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Nepveu
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000502:physiology; D012709:Serum Albumin / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D016896:Treatment Outcome; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D012709:Serum Albumin; D014867:Water
keywords: Antimalarial; High pressure homogenization; Human serum albumin; Indolone-N-oxides; Nanoparticles