Optimizing efficacy of amphotericin B through nanomodification

Abstract

Fungal infections and leishmaniasis are an important cause of morbidity and mortality in immunocompromised patients. The macrolide polyene antibiotic amphotericin B (AmB) has long been recognized as a powerful fungicidal and leishmanicidal drug. A conventional intravenous dosage form of AmB, AmB- deoxycholate (Fungizone or D-AmB), is the most effective clinically available for treating fungal and parasitic (leishmaniasis) infections. However, the clinical efficacy of AmB is limited by its adverse effects mainly nephrotoxicity. Efforts to lower the toxicity are based on synthesis of AmB analogues such as AmB esters or preparation of AmB-lipid associations in the forms of liposomal AmB (L-AmB or AmBisome), AmB lipid complex (Abelcet or ABLC), AmB colloidal dispersion (Amphocil or ABCD), and intralipid AmB. These newer formulations are substantially more expensive, but allow patients to receive higher doses for longer periods of time with decreased renal toxicity than conventional AmB. Modifications of liposomal surface in order to avoid RES uptake, thus increased targetability has been attempted. Emulsomes and other nanoparticles are special carrier systems for intracellular localization in macrophage rich organs like liver and spleen. Injectable nano-carriers have important potential applications as in site-specific drug delivery.

Figure 1

Several pathways by which lipid formulations of AmB are thought to reach fungal or parasitic cells.

Figure 2

Several pathways by which the lipid formulations of AmB may reach mammalian cells.

Figure 3

Proposed arrangement of AmB molecules (black) in the AmBisome bilayer. This structure accounts for the observation of rapid ion fluxes across the AmBisome bilayer in response to imposing a pH gradient from inside to outside. The individual AmB molecules form a “barrel” two of which fit tail-to-tail to form a pore spanning the bilayer. This structure is believed to contribute to the exceptional stability of AmBisome to loss of drug in buffer or plasma.

Figure 4

Antifungal activity of LNS-AmB, Fungizone, AmBisome, and DMSO-solubilized AmB in vitro. The growth inhibition of C. albicans was measured by the change in optical density at 540 nm in SD-MOPS broth after a 24-h incubation at 35°C. Results are the mean of two experiments. Adapted from Fukui et al (2003).

Figure 5

Survival of mice infected with C. albicans and treated with LNS-AmB, Fungizone, or AmBisome. Treatment was started 4 hours after fungal inoculation. +, P<0.05 compared with AmBisome; #, P<0.01 compared with Fungizone. Adapted from Fukui et al (2003).

Figure 6

Photographs showing geimsa stained splenic smears of hamster treated with emulsomes and control formulations. A-untreated control group; B-Mycol (AmB for injection) treated group; C-TLEs orTrilaurin based emulsomes treated group; D-TSEs or Tristearin based emulsomes treated group.