title: Therapy with sodium stibogluconate in stearylamine-bearing liposomes confers cure against SSG-resistant Leishmania donovani in BALB/c mice.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Jadavpur, Kolkata, India.
authors.forename: Jayeeta
authors.initials: J
authors.lastname: Roychoudhury
authors.forename: Roma
authors.initials: R
authors.lastname: Sinha
authors.forename: Nahid
authors.initials: N
authors.lastname: Ali
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology* / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004351:Drug Resistance / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism; D056724:Immunity, Humoral / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects; D007893:Leishmania donovani / Q000187:drug effects* / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D010713:Phosphatidylcholines / Q000737:chemistry; D020112:Rhodamine 123 / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D000588:Amines; D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D016207:Cytokines; D005452:Fluoresceins; D008081:Liposomes; D010713:Phosphatidylcholines; D020112:Rhodamine 123; D009569:Nitric Oxide; C045132:4-carboxyfluorescein; C009317:stearylamine; D000967:Antimony Sodium Gluconate