Therapy with Sodium Stibogluconate in Stearylamine-Bearing Liposomes Confers Cure against SSG-Resistant Leishmania donovani in BALB/c Mice
Open Access
- 10 March 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (3), e17376
- https://doi.org/10.1371/journal.pone.0017376
Abstract
Resistance of Leishmania donovani to pentavalent antimonials, the first-line treatment of visceral leishmaniasis (VL), has become a critical issue worldwide. Second-line and new drugs are also not devoid of limitations. Suitable drug-delivery systems can improve the mode of administration and action of the existing antimonials, thus increasing their clinical life. We investigated the efficacy of sodium stibogluconate (SSG) in phosphatidylcholine (PC)–stearylamine-bearing liposomes (PC-SA-SSG), PC-cholesterol liposomes (PC-Chol-SSG) and free amphotericin B (AmB) against SSG-resistant L. donovani strains in 8-wk infected BALB/c mice. Animals were sacrificed and parasites in liver, spleen and bone marrow were estimated 4-wk post-treatment by microscopic examination of stamp smears and limiting dilution assay. A set of PC-SA-SSG and AmB treated mice were further studied for protection against reinfection. Serum antibodies and cytokine profiles of ex-vivo cultured splenocytes were determined by ELISA. Uptake of free and liposomal SSG in intracellular amastigotes was determined by atomic absorption spectroscopy. Rhodamine 123 and 5-carboxyfluorescein, known substrates of Pgp and MRP transporter proteins, respectively, were used in free and liposomal forms for efflux studies to estimate intracellular drug retention. Unlike free and PC-Chol-SSG, PC-SA-SSG was effective in curing mice infected with two differentially originated SSG-unresponsive parasite strains at significantly higher levels than AmB. Successful therapy correlated with complete suppression of disease-promoting IL-10 and TGF-β, upregulation of Th1 cytokines and expression of macrophage microbicidal NO. Cure due to elevated accumulation of SSG in intracellular parasites, irrespective of SSG-resistance, occurs as a result of increased drug retention and improved therapy when administered as PC-SA-SSG versus free SSG. The design of this single-dose combination therapy with PC-SA-SSG for VL, having reduced toxicity and long-term efficacy, irrespective of SSG-sensitivity may prove promising, not only to overcome SSG-resistance in Leishmania, but also for drugs with similar resistance-related problems in other diseases.Keywords
This publication has 70 references indexed in Scilit:
- Combination Therapy with Paromomycin-Associated Stearylamine-Bearing Liposomes Cures Experimental Visceral Leishmaniasis through Th1-Biased ImmunomodulationAntimicrobial Agents and Chemotherapy, 2011
- Leishmania donovani Isolates with Antimony-Resistant but Not -Sensitive Phenotype Inhibit Sodium Antimony Gluconate-Induced Dendritic Cell ActivationPLoS Pathogens, 2010
- Drug Resistance in Visceral LeishmaniasisJournal of Biomedicine and Biotechnology, 2009
- A humanIL10BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcomeProceedings of the National Academy of Sciences of the United States of America, 2009
- Pentavalent Antimonials: New Perspectives for Old DrugsMolecules, 2009
- In Vitro Susceptibility of Field Isolates of Leishmania donovani to Miltefosine and Amphotericin B: Correlation with Sodium Antimony Gluconate Susceptibility and Implications for Treatment in Areas of EndemicityAntimicrobial Agents and Chemotherapy, 2009
- Leishmania donovaniinfection down-regulates TLR2-stimulated IL-12p40 and activates IL-10 in cells of macrophage/monocytic lineage by modulating MAPK pathways through a contact-dependent mechanismClinical and Experimental Immunology, 2008
- Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomyProceedings of the National Academy of Sciences of the United States of America, 2007
- Sodium Antimony Gluconate Induces Generation of Reactive Oxygen Species and Nitric Oxide via Phosphoinositide 3-Kinase and Mitogen-Activated Protein Kinase Activation inLeishmania donovani-Infected MacrophagesAntimicrobial Agents and Chemotherapy, 2006
- Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responsesNature Medicine, 2004