Abstract
Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.
Highlights
Fungal diseases affect over a billion people worldwide, being responsible for more than 1.5 million deaths each year [1]
Micelles made from an anionic dimeric lipoamino acid (LAA) derived from cysteine [167], as well as equimolar mixtures of this LAA and either sodium cholate or sodium deoxycholate [168], were able to solubilize Amphotericin B (AmB) in its monomeric and less toxic form, under biomimetic conditions [168]
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]
Summary
Fungal diseases affect over a billion people worldwide, being responsible for more than 1.5 million deaths each year [1]. Life-threatening invasive candidiasis and invasive aspergillosis are among the most common healthcare-associated infections (HAIs), requiring longer hospitalization stay and often expensive antifungal drugs, contributing to increased healthcare costs [7,9,10]. Decreased susceptibility to antifungal drugs results in higher minimum inhibitory concentration (MIC) values for microbial strains grown as biofilms compared to their corresponding planktonic forms [15]. This often hampers therapeutic options and contributes to the emergence and spread of antibiotic resistance [12]. Despite being part of the WHO list of essential medicines since 2013, AmB is still not available in many countries, including some where fungal diseases have high mortality rates [4]
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