Development of drug-loaded immunoliposomes for the selective targeting and elimination of rosetting Plasmodium falciparum-infected red blood cells.
Parasite proteins exported to the surface of Plasmodium falciparum-parasitized red blood cells (pRBCs) have a major role in severe malaria clinical manifestation, where pRBC cytoadhesion and rosetting processes have been strongly linked with microvascular sequestration while avoiding both spleen filtration and immune surveillance. The parasite-derived and pRBC surface-exposed PfEMP1 protein has been identified as one of the responsible elements for rosetting and, therefore, considered as a promising vaccine candidate for the generation of rosette-disrupting antibodies against severe malaria. However, the potential role of anti-rosetting antibodies as targeting molecules for the functionalization of antimalarial drug-loaded nanovectors has never been studied. Our manuscript presents a proof-of-concept study where the activity of an immunoliposomal vehicle with a dual performance capable of specifically recognizing and disrupting rosettes while simultaneously eliminating those pRBCs forming them has been assayed in vitro. A polyclonal antibody against the NTS-DBL1α N-terminal domain of a rosetting PfEMP1 variant has been selected as targeting molecule and lumefantrine as the antimalarial payload. After 30min incubation with 2μM encapsulated drug, a 70% growth inhibition for all parasitic forms in culture (IC50: 414nM) and a reduction in ca. 60% of those pRBCs with a rosetting phenotype (IC50: 747nM) were achieved. This immunoliposomal approach represents an innovative combination therapy for the improvement of severe malaria therapeutics having a broader spectrum of activity than either anti-rosetting antibodies or free drugs on their own.
Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Institute for Global Health (ISGlobal), Barcelona Center for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain. Electronic address: ernest.moles@isglobal.org.
Ernest
E
Moles
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Kirsten
K
Moll
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Department of Microbiology, National University of Singapore, Singapore.
Jun-Hong
JH
Ch'ng
Department of Laboratory Medicine (LABMED), H5, Division of Clinical Chemistry, Karolinska Institutet, Huddinge, Sweden.
Paolo
P
Parini
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
Mats
M
Wahlgren
Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Institute for Global Health (ISGlobal), Barcelona Center for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain. Electronic address: xfernandez_busquets@ub.edu.
Xavier
X
Fernàndez-Busquets
D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D000962:Antimalarials / Q000008:administration & dosage* / Q000494:pharmacology; D002478:Cells, Cultured; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D008081:Liposomes; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology*; D012397:Rosette Formation
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D000962:Antimalarials; D008081:Liposomes; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
Combination therapy; DSPC (PubChem CID: 94,190); Immunoliposomes; Lumefantrine (PubChem CID: 6,437,380); Malaria; Maleimide (PubChem CID: 10,935); Nanomedicine; Rosetting; SATA (PubChem CID: 127,532); Targeted drug delivery