Hemisynthetic trifluralin analogues incorporated in liposomes for the treatment of leishmanial infections.
Leishmaniasis, a vector-borne parasitic disease caused by Leishmania protozoa, is one of the most neglected tropical diseases in terms of drug discovery and development. Current treatment is based on a limited number of chemotherapeutic agents all of which present either/or resistance issues, severe toxicities and adverse reactions associated with extended treatment regimens, and high cost of therapy. Dinitroanilines are a new class of drugs with proven in vitro antileishmanial activity. In previous work a liposomal formulation of one dinitroaniline (TFL) was found to be active against Leishmania parasites in a murine model of visceral leishmaniasis (VL) and in the treatment of experimental canine leishmaniasis. In this study we have investigated the use of dinitroaniline analogues (TFL-A) associated to liposomes, as means to further improve TFL antileishmanial activity. The potential of the liposomal formulations was assessed in vitro against Leishmania infantum promastigotes and intracellular amastigotes and in vivo in a murine model of zoonotic VL. Free and liposomal TFL-A were active in vitro against Leishmania parasites, and they also exhibited reduced cytotoxicity and haemolytic activity. Treatment of infected mice with liposomal TFL-A reduced the amastigote loads in the spleen up to 97%, compared with the loads for untreated controls. These findings illustrate that chemical synthesis of new molecules associated with the use of Nano Drug Delivery Systems that naturally target the diseased organs could be a promising strategy for effective management of VL.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: mcarvalheiro@ff.ulisboa.pt.
Manuela
M
Carvalheiro
Solar Energy Unit, National Laboratory for Energy and Geology (LNEG), Estrada do Paço do Lumiar, 1649-038 Lisbon, Portugal.
M Alexandra
MA
Esteves
Unidade de Ensino e Investigação de Parasitologia Médica and Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
David
D
Santos-Mateus
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Rui M
RM
Lopes
Unidade de Ensino e Investigação de Parasitologia Médica and Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
M Armanda
MA
Rodrigues
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Carla V
CV
Eleutério
Laboratory of Clinical Bacteriology, School of Medicine, University of Crete, 71003 Heraklion, Greece.
Effie
E
Scoulica
Unidade de Ensino e Investigação de Parasitologia Médica and Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
Gabriela
G
Santos-Gomes
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: eugeniacruz@ff.ulisboa.pt.
M Eugénia M
ME
Cruz
D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D013154:Spleen / Q000469:parasitology; D013678:Technology, Pharmaceutical / Q000379:methods; D014274:Trifluralin / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000633:toxicity
D000981:Antiprotozoal Agents; D008055:Lipids; D008081:Liposomes; D014274:Trifluralin
Dinitroaniline analogues; Drug delivery; Leishmania; Liposomes