Abstract
BackgroundResistance 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.Methodology/Principal FindingsWe 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.Conclusions/SignificanceThe 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.
Highlights
Leishmaniasis is a disease caused by different species of protozoa of the genus Leishmania that are transmitted by Phlebotomine sandflies
Therapeutic potency of PC-SA-sodium stibogluconate (SSG) was compared with other formulations in susceptible BALB/c mice infected with virulent strains of SSG-resistant L. donovani, GE1F8R and CK1R, to validate the strain-independent efficacy of PC-SA-SSG
Therapy with a single dose of SSG in PC-SA liposomes led to the successful cure of progressive SSG-resistant visceral leishmaniasis (VL) in BALB/c mice that was even better than amphotericin B (AmB) therapy in providing effective antileishmanial immunity and strong protection against reinfection
Summary
Leishmaniasis is a disease caused by different species of protozoa of the genus Leishmania that are transmitted by Phlebotomine sandflies. It has traditionally been classified in three different clinical forms, visceral (VL), cutaneous (CL) and mucocutaneous leishmaniasis (MCL), which have different immunopathologies and degrees of morbidity and mortality. Approaches to overcome antimonial resistance include use of alternative drugs which as mentioned earlier, are not devoid of limitations, or combination therapy having synergistic effects to check the further development of resistance [8,9,10,11,12]. Resistance of Leishmania donovani to pentavalent antimonials, the first-line treatment of visceral leishmaniasis (VL), has become a critical issue worldwide. Suitable drugdelivery systems can improve the mode of administration and action of the existing antimonials, increasing their clinical life
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