Antileishmanial activity, pharmacokinetics and tissue distribution studies of mannose-grafted amphotericin B lipid nanospheres.

摘要

Leishmania parasite resides mainly in the liver and the spleen and multiplies. Effective therapy of leishmaniasis could be achieved by delivering antileishmanial drugs to these sites. Present investigations were aimed at developing lipid nanospheres of amphotericin B (LN-A) anchored with mannose to achieve targeted delivery to the liver. Mannose is specifically involved in the recognition of parasite or appropriate ligands on the macrophage surface LN-A, and mannose-anchored lipid nanospheres (LN-A-MAN) were prepared by homogenization followed by ultrasonication method. Particle size and zeta potential were measured using Malvern Zetasizer. The average particle size after sterilization of LN-A and LN-A-MAN ranged from 193.4 +/- 1.1 to 775.8 +/- 9.1. Leishmaniasis was induced in BALB/c mice by injecting Leishmania donovani parasites intravenously. Infected mice were administered with a single dose (5 mg/kg body weight) of LN-A, LN-A-MAN, and Fungizone (marketed product).The efficacy of the formulations was evaluated by measuring the reduction in parasite burden. Fungizone reduced 82 and 69%, LN-A reduced 90 and 85%, LN-A-MAN reduced 95 and 94% of parasite burden in the liver and the spleen, respectively. LN-A and LN-A-MAN-treated mice did not show any elevation in serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), urea, and creatinine levels as compared with Fungizone. Pharmacokinetic parameters were estimated and the concentration of amphotericin B (AmB) in mice plasma declined biexponentially and AmB concentrations were significantly higher for LN-A- and LN-A-MAN than Fungizone-treated mice (P < 0.05). Tissue distribution patterns were studied in different tissues such as the liver, the spleen, the kidney, and the brain of BALB/c mice. LN-A-MAN was found to distribute more rapidly to the liver and the spleen explaining the reason for higher antileishmanial activity.