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. 2006 Apr;50(4):1238-44.
doi: 10.1128/AAC.50.4.1238-1244.2006.

Nanodisk-associated amphotericin B clears Leishmania major cutaneous infection in susceptible BALB/c mice

Keith G Nelson  1 , Jeanette V Bishop, Robert O Ryan, Richard Titus
Affiliations

Nanodisk-associated amphotericin B clears Leishmania major cutaneous infection in susceptible BALB/c mice

Keith G Nelson et al. Antimicrob Agents Chemother. 2006 Apr.

Abstract

Nanometer-scale, apolipoprotein-stabilized phospholipid bilayer disk complexes (nanodisks [ND]) harboring the toxic and poorly soluble antileishmanial agent amphotericin B (AMB) were examined for efficacy in treatment of Leishmania major-infected BALB/c mice (Mus musculus). L. major-infected mice were intraperitoneally (i.p.) treated with AMB-ND in 0-, 1-, and 5-mg/kg doses at 24 h, 48 h, and 4, 7, 14, and 21 days postinfection in two experiments. L. major-infected mice were i.p. treated with phosphate-buffered saline, 5 mg/kg AMB-ND, or 5 mg/kg lipid-associated amphotericin B (liposomal amphotericin B, AmBisome) at 24 h, 48 h, and 10, 20, 30, and 40 days postinfection in one experiment. Parasite numbers, footpad lesion size progression, and development of cytokine responses were assayed at days 7, 15, 30, 50, 140, and 250 or at days 14, 30, 50, 95, and 140 postinfection. Mice administered AMB-ND in 1- or 5-mg/kg doses were significantly protected from L. major, displaying decreases in lesion size and parasite burden, particularly at the 5-mg/kg dosage level. In contrast to the i.p. treated AmBisome group, BALB/c mice treated with i.p. AMB-ND completely cleared an L. major infection by 140 to 250 days postinfection, with no lesions remaining and no parasites isolated from infected animals. Restimulated mixed lymphocyte culture cytokine responses (interleukin-4 [IL-4], IL-12, IL-10, NO, and gamma interferon) were unchanged by AMB-ND administration compared to controls. The marked clearance of Leishmania parasites from a susceptible strain of mice without an appreciable change in the cytokine response suggests that AMB-ND represent a potentially useful formulation for treatment of intrahistiocytic organisms.

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Figures

FIG. 1.
FIG. 1.
Effects of AMB-ND treatment on disease progression in L. major-infected BALB/c mice. Mice were infected with 1 × 106 LV39 L. major promastigotes and treated at 24 h, 48 h, 7 days, 14 days, and 21 days postinfection with empty ND or AMB-ND (0, 1, or 5 mg/kg AMB per treatment). Values are averaged from multiple (n = 2) experiments utilizing identical parameters. (A) Effect of AMB-ND treatment on footpad lesion size in L. major-infected BALB/c mice. Footpad lesion size was measured at the indicated time points. Values plotted are the means ± standard deviations of 4 to 20 measurements. (B) Effect of AMB-ND treatment on parasite burden in L. major-infected BALB/c mice. Parasite numbers per footpad were determined as described in Materials and Methods from samples obtained at the indicated time points. Values reported are the means ± 95% confidence limits of parasite numbers based on limiting-dilution analysis as described in Material and Methods.
FIG. 2.
FIG. 2.
Effect of AMB formulation on disease progression in L. major-infected BALB/c mice. Groups of mice were infected with 1 × 106 LV39 L. major promastigotes and treated at 24 h, 48 h, 10 days, 20 days, 30 days, and 40 days with PBS (control), 5 mg/kg AMB in AmBisome, or 5 mg/kg AMB in AMB-ND. Data are derived from a single experiment (n = 1). (A) Effect of AMB formulation on footpad lesion size in L. major-infected BALB/c mice. Footpad lesion size was measured at the indicated time points. Values plotted are the means ± standard deviations of 2 to 14 measurements. (B) Effect of AMB formulation on parasite numbers per footpad in L. major-infected BALB/c mice. Parasite numbers per footpad were determined as described in Materials and Methods from samples obtained at the indicated time points. Values reported are the means ± 95% confidence limits of parasite numbers based on limiting-dilution analysis as described in Material and Methods.
FIG. 3.
FIG. 3.
Immunoblot of L. major antigens. L. major promastigote lysate proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. The membrane was probed with anti-L. major BALB/c mouse serum collected 50 days following inoculation with 1 × 106 LV39 Lm promastigotes and subsequent treatment with PBS (control), AmBisome (3 mg/kg or 5 mg/kg AMB), or AMB-ND (3 mg/kg or 5 mg/kg AMB) at 24 h, 48 h, 10 days, 20 days, 30 days, and 40 days. Images collected with Adobe Photoshop 6.0 and Windows Powerpoint 2003.
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