Amphotericin BGum Arabic Conjugates Synthesis T

Authors: K K Nishi M Antony P V Mohanan T V Anilkumar P M Loiseau A Jayakrishnan

Publish Date: 2007/03/20

Volume: 24, Issue: 5, Pages: 971-980

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Abstract

Gum arabic a branched polysaccharide consisting of more than 90 arabinogalactan having a molecular weight around 250000 Da is the oldest and best known of all natural gums The objective of the present investigation was to examine whether amphotericin B AmB the polyene antibiotic when conjugated to periodate oxidized gum arabic still retained its antifungal and antileishmanial activity and to evaluate its toxicity and bioavailabilityAmB conjugated to the oxidized polysaccharide through Schiff’s linkages in the unreduced imine and reduced amine forms were characterized for the drug content hemolytic potential molecular mass in vitro release and were examined for antifungal activity against Candida albicans and Cryptococcus neoformans and for antileishmanial activity against promastigotes of Leishmania donovani in culture Toxicity and bioavailability were evaluated by intravenous iv injections of the conjugates in mice and rabbits respectivelyThe conjugates were found to be nonhemolytic and mice withstood a dosage of 20 mg AmB/kg body weight of both conjugates Histological examination of the internal organs of mice showed no lesions in kidney brain heart or liver Estimation of the residual drug in the internal organs 7 days post injection showed that the spleen still retained 84 ± 053 μg/g of tissue AmB was found to be released from both conjugates in vitro although the release from the imine conjugate was much faster than from the amine conjugate The concentrations inhibiting parasite growth by 50 IC50 values for the imine conjugate against promastigotes of L donovani LV9 and DD8 strains were 037 ± 004 and 144 ± 018 μM respectively The IC50 values for the amine conjugates were much higher The minimum inhibitory concentration MIC against C albicans and C neoformans was in the range of 05–09 μg/mL for both imino and amino conjugates The bioavailability of the conjugate in rabbits showed that the imine conjugate maintained a plasma concentration in the range of 20 to 5 μg/mL while for the amine conjugate it was in the range of 17 to 3 μg/mL over 24 hThe drug conjugates were stable nonhemolytic and nontoxic to the internal organs of the animal and showed good antifungal and antileishmanial activity in vitro In spite of the large molecular weight of the polysaccharide AmB from the conjugates showed bioavailability after iv injection Since the highest concentration of AmB was found in the spleen after a single injection these conjugates may have potential in antileishmanial therapyK K Nishi thanks the University Grants Commission New Delhi for a senior research fellowship Thanks are due to Dr Nirmala R James for the hemolysis experiments and many useful discussions Thanks are also due to the Director SCTIMST for permission to publish this manuscript

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