Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

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.

Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached?

“…However, its widespread use is hampered by its toxicity and costs associated with the better-tolerated lipid formulations. Due to the poor solubility in water and membrane permeability of AmB itself, detergents like the bile salt sodium deoxycholate need to be used for administration [11,25]. Efficacy, as well as partly toxicity, is mediated via the interaction of AmB with sterols of biomembranes of fungal and human cells (i.e., ergosterol and cholesterol) leading to increased cell permeability via pore-forming ion channels, cell leakage, rupture, and eventually cell death [11,26,27].…”

“…Due to the poor solubility in water and membrane permeability of AmB itself, detergents like the bile salt sodium deoxycholate need to be used for administration [11,25]. Efficacy, as well as partly toxicity, is mediated via the interaction of AmB with sterols of biomembranes of fungal and human cells (i.e., ergosterol and cholesterol) leading to increased cell permeability via pore-forming ion channels, cell leakage, rupture, and eventually cell death [11,26,27]. Immunomodulatory effects of AmB promote the release of pro-inflammatory mediators and contribute to toxic side effects such as acute infusion-related reactions (e.g., fever, chills, headache, nausea, vomiting, hypotension, arrhythmia) and nephrotoxicity [26,28,29].…”

“…Moreover, the lack of drug accumulation in organs [13] may contribute to increased compatibility. In recent years, several nanotechnology-lipid-based drug delivery systems, including lipid conjugates, micelles, liposomes, ethosomes, and niosomes, nanoemulsions, SEDDSs (Self-Emulsifying Drug Delivery Systems), cubosomes, nanodisks, SLNs (Solid Lipid Nanoparticles and Nanostructured Lipid Carriers), and lipid-polymer hybrid nanoparticles have been investigated [11]. They all have in common to overcome the need for parenteral administration of AmB, to reduce its toxicity, but to preserve or even improve its efficacy.…”

“…Moreover, cochleates are engulfed by macrophages, which facilitates to reach the infected area. Once inside, as a response to the low calcium levels of the cytoplasm, the cochleate structure destabilizes, opens, and liberates the cargo molecule [5,11]. However, the quantity of cations in serum and mucosal secretions in vivo preserves the shape of the cochleate drug crystal [12].…”

In Vitro Evaluation of Self-Nano-Emulsifying Drug Delivery Systems (SNEDDS) Containing Room Temperature Ionic Liquids (RTILs) for the Oral Delivery of Amphotericin B

“…AmpB is a polyene antifungal antibiotic and belongs to BCS Class IV, which is characterized by a low permeability and low solubility [12]. This drug remains the most effective antifungal medication for severe fungal infections and visceral Leishmaniasis [13]. Worldwide, 12-15 million people are infected with visceral Leishmaniasis, and it is estimated that 70,000 deaths are caused every year [14].…”