title: Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells.
abstract: Heparin had been demonstrated to have antimalarial activity and specific binding affinity for Plasmodium-infected red blood cells (pRBCs) vs. non-infected erythrocytes. Here we have explored if both properties could be joined into a drug delivery strategy where heparin would have a dual role as antimalarial and as a targeting element of drug-loaded nanoparticles. Confocal fluorescence and transmission electron microscopy data show that after 30 min of being added to living pRBCs fluorescein-labeled heparin colocalizes with the intracellular parasites. Heparin electrostatically adsorbed onto positively charged liposomes containing the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane and loaded with the antimalarial drug primaquine was capable of increasing three-fold the activity of encapsulated drug in Plasmodium falciparum cultures. At concentrations below those inducing anticoagulation of mouse blood in vivo, parasiticidal activity was found to be the additive result of the separate activities of free heparin as antimalarial and of liposome-bound heparin as targeting element for encapsulated primaquine.
  
  
  BACKGROUND
  Malaria remains an enormous global public health concern. In this study, a novel functionalized heparin formulation used as drug delivery agent for primaquine was demonstrated to result in threefold increased drug activity in cell cultures, and in a murine model it was able to provide these benefits in concentrations below what would be required for anticoagulation. Further studies are needed determine if this approach is applicable in the human disease as well.
authors.affiliation: Nanomalaria Unit, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Nanomalaria Unit, Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Marques
authors.affiliation: Nanomalaria Unit, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Nanomalaria Unit, Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain.
authors.forename: Ernest
authors.initials: E
authors.lastname: Moles
authors.affiliation: Nanomalaria Unit, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Nanomalaria Unit, Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Urbán
authors.affiliation: Unitat de Polimorfisme i Calorimetria, Centres Científics i Tecnològics, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Rafel
authors.initials: R
authors.lastname: Prohens
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, University of Barcelona, Barcelona, Spain.
authors.forename: Maria Antònia
authors.initials: MA
authors.lastname: Busquets
authors.affiliation: Interfacultary Research Center of Biomaterials (CEIB), University of Liège, Chemistry Institute, Liège (Sart-Tilman), Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sevrin
authors.affiliation: Interfacultary Research Center of Biomaterials (CEIB), University of Liège, Chemistry Institute, Liège (Sart-Tilman), Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Grandfils
authors.affiliation: Nanomalaria Unit, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain; Nanomalaria Unit, Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain. Electronic address: xfernandez_busquets@ub.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fernàndez-Busquets
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use*; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000469:parasitology*; D006493:Heparin / Q000737:chemistry* / Q000627:therapeutic use*; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D010963:Plasmodium falciparum / Q000472:pathogenicity*
chemical_list: D000962:Antimalarials; D008081:Liposomes; D006493:Heparin
keywords: Heparin; Liposomes; Malaria; Plasmodium; Targeted drug delivery