title: Miltefosine lipid nanocapsules: Intersection of drug repurposing and nanotechnology for single dose oral treatment of pre-patent schistosomiasis mansoni.
abstract: A dual drug repurposing/nanotechnological approach was used to develop an alternative oral treatment for schistosomiasis mansoni using miltefosine (MFS), an anticancer alkylphosphocholine, and lipid nanocapsules (LNCs) as oral nanovectors. We demonstrated earlier that MFS possesses significant activity against different developmental stages of Schistosoma mansoni in the mouse model using 5 successive 20mg/kg/day oral doses. Moreover, an effective single dose (20mg/kg) oral treatment against the adult stage of S. mansoni in mice was developed using LNCs, particularly modified with CTAB, a positive charge imparting agent (MFS-LNC-CTAB(+)), or oleic acid as membrane permeabilizer (MFS-LNC-OA). Efficacy enhancement involved, at least in part, targeting of the worm tegument with MFS-LNCs as a new therapeutic entity. As the tegument surface charge and composition may differ in pre-patent stages of the parasite, it was of importance in the present study to assess the efficacy of a single oral dose of the two MFS-LNC formulations against invasive and immature stages for potential advantage relative to praziquantel. Results indicated potent schistosomicidal effects against both invasive and immature stages of S. mansoni in infected mice, efficacy being both formulation and developmental stage dependent. This was indicated by the significant reduction in the total worm burden of the invasive stage by 91.6% and 76.8% and the immature stage by 82.7% and 96.7% for MFS-LNC-CTAB+ and MFS-LNC-OA, respectively. Histopathological findings indicated amelioration of hepatic pathology with regression of the granulomatous inflammatory reaction and reduction in granulomas number and size, verifying marked improvement in architecture of hepatic lobules. From a clinical perspective, MFS-LNCs offer potential as an alternative single oral dose nanomedicine with a wide therapeutic profile for the mass chemotherapy of schistosomiasis mansoni.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Riham M
authors.initials: RM
authors.lastname: El-Moslemany
authors.affiliation: Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Egypt. Electronic address: mahaeissa19@yahoo.com.
authors.forename: Maha M
authors.initials: MM
authors.lastname: Eissa
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Alyaa A
authors.initials: AA
authors.lastname: Ramadan
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Egypt.
authors.forename: Labiba K
authors.initials: LK
authors.lastname: El-Khordagui
authors.affiliation: Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Egypt.
authors.forename: Mervat Z
authors.initials: MZ
authors.lastname: El-Azzouni
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D058492:Drug Repositioning; D006099:Granuloma / Q000473:pathology; D008099:Liver / Q000469:parasitology; D051379:Mice; D053769:Nanocapsules / Q000627:therapeutic use*; D036103:Nanotechnology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011223:Praziquantel / Q000627:therapeutic use*; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy*; D012556:Schistosomicides / Q000627:therapeutic use*
chemical_list: D053769:Nanocapsules; D012556:Schistosomicides; D010767:Phosphorylcholine; C039128:miltefosine; D011223:Praziquantel
keywords: Histopathology; Immature stages; Lipid nanocapsules; Miltefosine; Schistosoma mansoni; Worm burden