title: Use of poly(amidoamine) drug conjugates for the delivery of antimalarials to Plasmodium.
abstract: Current malaria therapeutics demands strategies able to selectively deliver drugs to Plasmodium-infected red blood cells (pRBCs) in order to limit the appearance of parasite resistance. Here, the poly(amidoamines) AGMA1 and ISA23 have been explored for the delivery of antimalarial drugs to pRBCs. AGMA1 has antimalarial activity per se as shown by its inhibition of the in vitro growth of Plasmodium falciparum, with an IC₅₀ of 13.7 μM. Fluorescence-assisted cell sorting data and confocal fluorescence microscopy and transmission electron microscopy images indicate that both polymers exhibit preferential binding to and internalization into pRBCs versus RBCs, and subcellular targeting to the parasite itself in widely diverging species such as P. falciparum and Plasmodium yoelii, infecting humans and mice, respectively. AGMA1 and ISA23 polymers with hydrodynamic radii around 7 nm show a high loading capacity for the antimalarial drugs primaquine and chloroquine, with the final conjugate containing from 14.2% to 32.9% (w/w) active principle. Intraperitoneal administration of 0.8 mg/kg chloroquine as either AGMA1 or ISA23 salts cured P. yoelii-infected mice, whereas control animals treated with twice as much free drug did not survive. These polymers combining into a single chemical structure drug carrying capacity, low unspecific toxicity, high biodegradability and selective internalization into pRBCs, but not in healthy erythrocytes for human and rodent malarias, may be regarded as promising candidates deserving to enter the antimalarial therapeutic arena.
authors.affiliation: Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Urbán
authors.affiliation: Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Valle-Delgado
authors.affiliation: Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, IT-20133 Milano, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Mauro
authors.affiliation: Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Marques
authors.affiliation: Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, IT-20133 Milano, Italy.
authors.forename: Amedea
authors.initials: A
authors.lastname: Manfredi
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.affiliation: Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, IT-20133 Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ranucci
authors.affiliation: Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, IT-20133 Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ferruti
authors.affiliation: Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Baldiri Reixac 10-12, ES-08028 Barcelona, Spain; Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Rosselló 149-153, ES-08036 Barcelona, Spain; Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, ES-08028 Barcelona, Spain. Electronic address: xfernandez_busquets@ub.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fernàndez-Busquets
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry; D002738:Chloroquine / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004912:Erythrocytes / Q000187:drug effects / Q000382:microbiology; D005260:Female; D008288:Malaria / Q000188:drug therapy* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018512:Parasitemia / Q000188:drug therapy / Q000382:microbiology; D010961:Plasmodium / Q000187:drug effects / Q000254:growth & development; D011073:Polyamines / Q000008:administration & dosage* / Q000737:chemistry; D011319:Primaquine / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000962:Antimalarials; D004337:Drug Carriers; C531249:Poly(amidoamine); D011073:Polyamines; D002738:Chloroquine; D011319:Primaquine
keywords: Plasmodium; malaria; nanomedicine; polyamidoamines; polymer–drug carriers; targeted drug delivery