Nanoemulsions loaded with amphotericin B: A new approach for the treatment of leishmaniasis

Abstract

This work aimed to develop nanoemulsions (NE) containing cholesterol and Amphotericin B (AmB) evaluating the influence of a lipophilic amine (stearylamine; STE) on drug encapsulation efficiency (EE), cytotoxicity on macrophages and in vitro antileishmanial activity. The EE of AmB in NE was nearly 100% regardless of STE concentration. Stability studies showed that AmB-loaded NE with or without STE were stable revealing that AmB content and EE remained constant after 180days. In significant contrast, the EE for AmB in NE without cholesterol drastically decreased showing that this co-surfactant significantly improved the retention of drug in NE. The electronic absorption and circular dichroism (CD) data revealed that the signal characteristic of self-associated free AmB, the most toxic form to the host cells, was virtually absent in the spectra of AmB-loaded NE. In agreement, NE-induced toxicity toward macrophages was significantly lower than that observed for the conventional AmB. STE enhanced both cytotoxicity and the activity against intracellular amastigotes of AmB-loaded NE. However, selectivity index values for AmB-loaded NE were considerably higher than that observed for conventional AmB. AmB-loaded and cholesterol-stabilized NE constitutes an attractive alternative for the treatment of leishmaniasis.

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…The promising results indicate that AmB-NEs may be a potential strategy in the i.v. treatment against leishmaniasis, which can be seen as an outstanding evolution from previous studies concerning dermal treatment of AmB-loaded NEs [180,221].…”

“…therapy of leishamaniasis, in vitro activity against intracellular amastigotes and in vitro cytotoxicity on J774 murine macrophages were evaluated. In the formulation with Sta, cytotoxicity increased with the cationic lipid concentration, resulting from the electrostatic interaction of Sta with anionic constituents of the cell membrane [180]. But when compared to conventional AmB, the NEs showed a lower cytotoxicity probably due to the observed reduction of the self-associated free drug in AmB lipid vehicles.…”

“…Nanoemulsions (NEs) are formulation strategies that enhance the solubility and the bioavailability of AmB [180]. NEs are O/W dispersions having nanosized droplets with high surface area that obey the prerequisite for enhanced adherence to the fungal cell surface, besides providing benefits in terms of preparation, drug solubilization, and controlled release [181][182][183][184].…”

“…Based on a strategy that uses the pH-solubility profile of the drug to formulate AmB-loaded NEs, Caldeira et al prepared NEs containing AmB and cholesterol and studied the effect of the cationic lipid stearylamine (Sta) on drug encapsulation efficiency (EE), cytotoxicity towards macrophages and in vitro antileishmania activity [180]. The stability of NEs containing AmB can be thus accomplished from the production of an ion pairing between AmB and Sta (with intrinsic antileishmanial activity) [180,221]. Sta concentration did not affect EE, which turned out to be approximately 100%, nor the stability of the nanoformulation.…”

“…Semisolid AmB topical formulations with added γ-CD showed shear-thinning and thixotropic behavior, improved skin permeability, and enhanced in vitro antifungal efficacy against Candida species and Sacharomyces cerevisiae compared with an AmB reference formulation containing no solubility enhancers [224]. Several studies on NE development for topical AmB delivery have shown their suitability for the treatment of skin fungal infections [180][181][182][183][184], based on the synergistic effects resulting from the combination of lipids and surfactants with the antifungal drug [181]. Hussein and co-workers evaluated the enhanced stability and permeation capacity of AmB-loaded NEs at varying pH, storage temperature, and skin permeation of AmB [181].…”