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JAC Advance Access originally published online on May 26, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):60-68; doi:10.1093/jac/dkh281
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

Targeting Leishmania (L.) chagasi amastigotes through macrophage scavenger receptors: the use of drugs entrapped in liposomes containing phosphatidylserine

André Gustavo Tempone1, Daniel Perez2, Susanne Rath3, André Luis Vilarinho3, Renato A. Mortara4 and Heitor Franco de Andrade, Jr2,*

1 Instituto de Ciências Biomédicas, Dept. Parasitologia - Universidade de São Paulo; 2 Instituto de Medicina Tropical – Lab. Protozoologia, Universidade de São Paulo, Av. Dr Enéas de Carvalho Aguiar, 470 Cerqueira César, 05403–000 São Paulo; 3 Dept. Química Analítica, Instituto de Química -Unicamp; 4 Dept. Microbiologia, Imunologia e Parasitologia – Escola Paulista de Medicina UNIFESP, Brazil

* Corresponding author. Tel: +55-11-3066-7010; Fax: +55-11-3088-5237; Email: hfandrad{at}usp.br

Objectives: We devised liposome-entrapped antimony with the negatively charged lipid phosphatidylserine—liposome-entrapped antimony (Sb-LP)—in order to improve their targeting to infected macrophages through the interaction with scavenger receptors (SRs).

Methods: SR production was indirectly evaluated by its mRNA synthesis in infected and uninfected peritoneal macrophages using RT–PCR. The interaction and cytotoxicity of Sb-LP with SRs and their metabolism were determined by incubation with macrophages in the presence of cytochalasin B, chloroquine or different competitive ligands, with determination of the 50% inhibitory concentration (IC50) in vitro in infected macrophages. The intracellular trafficking of Sb-LP was evaluated by confocal microscopy using trapped fluorescent dyes.

Results: Our results showed an up-regulation of macrophage SR mRNA during the initial steps of Leishmania (L.) chagasi infection. By competitive ligand assays, we demonstrated the preferential uptake of Sb-LP by macrophage SRs. Sb-LP was 16-fold more effective (IC50=14.11 µM) than the free drug (IC50=225.9 µM) against L. (L.) chagasi-infected macrophages. The binding and uptake of Sb-LP in macrophages were shown to be energy-dependent and were reduced in the presence of cytochalasin B, showing the dependency of the cell microfilament system. Confocal analysis using trapped fluorescent dyes showed fluorescence of parasites or in their close proximity, compatible with the localized delivery of the liposomes.

Conclusions: The uptake of Sb-LP was reduced in infected macrophages, despite their effectiveness and targeting ability, suggesting a low metabolic rate in infected macrophages that could be overcome by the higher efficiency of the liposomal formulation. These in vitro results suggest that liposomes could improve the therapeutic index of old drugs, such as pentavalent antimony, via targeted delivery to Leishmania-infected cells.

Keywords: leishmaniasis , antimony , parasitophorous vacuoles , therapy


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