Efficacy and toxicity evaluation of new amphotericin B micelle systems for brain fungal infections

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…The antibiotic targets the cellular membrane, showing higher affinity for ergosterol-containing membranes typical of fungal cells than for cholesterol-containing membranes of mammalian host cells [44,53,54]. AmB oligomers are particularly toxic to eukaryotic cells leading to high antifungal activity but also severe toxic side effects [43][44][45][46]48,49,51,55] while polyaggregated and monomeric forms of the drug retain antifungal activity and show reduced toxicity towards host cells [43,49,51]. This suggests that better selectivity for fungal cells leading to improved therapeutic index may be achieved by carefully controlling the aggregation state of the drug [25,43,45,46], which can be easily determined from AmB ultraviolet (UV) absorption or fluorescence spectra that are sensitive to different aggregation states [46,56].…”

“…Disruption of ergosterol biosynthesis is responsible for resistance to Due to its amphipathic nature, AmB is able to self-associate in aqueous solution forming water soluble dimers and oligomers that can further associate to form insoluble polyaggregates, which act as a monomer reservoir [25,[43][44][45][46]. The nature and proportion of each species in both aqueous and lipid phases is dependent on total drug concentration, temperature, type of formulation, and membrane composition, being correlated with AmB efficacy and toxicity [43][44][45][46][47][48][49][50][51]. Drug morphology (crystalline or amorphous state) and formulation techniques also influence the rate of dissolution and solubility of AmB [52].…”

Efficacy, Biodistribution, and Nephrotoxicity of Experimental Amphotericin B-Deoxycholate Formulations for Pulmonary Aspergillosis

“…Liposomal amphotericin B (LAMB) is the "gold standard" in aspergillosis therapy (1,3). Several studies have demonstrated that the large particle sizes of different AMB formulations are related to high nephrotoxicity (4)(5)(6)(7). Commercial dimeric deoxycholate (DCH)-amphotericin B (D-AMB) shows a high percentage of small particles (56.2 Ϯ 4.3 nm) and a small percentage of large particles (around 4.0 m) (6), the latter related to nephrotoxicity (4)(5)(6)(7).…”

“…Several studies have demonstrated that the large particle sizes of different AMB formulations are related to high nephrotoxicity (4)(5)(6)(7). Commercial dimeric deoxycholate (DCH)-amphotericin B (D-AMB) shows a high percentage of small particles (56.2 Ϯ 4.3 nm) and a small percentage of large particles (around 4.0 m) (6), the latter related to nephrotoxicity (4)(5)(6)(7). LAMB, the reference commercial formulation, with a polyaggregated AMB form, shows a small particle size (around 100 nm) that enhances antifungal efficacy and diminishes drug toxicity (8), while other lipid complexes marketed as Abelcet (ABLC) present polyaggregated AMB with a particle size of 1.6 to 11 m (7).…”

“…In previous studies, it has been observed that polyaggregated systems of AMB with sodium deoxycholate are a safer and less toxic form than D-AMB, with the same proportion of DCH, when administered intravenously (i.v.) (6,11). The AMB distribution to organs with high presence of macrophages and organs of the reticuloendothelial system like liver and spleen is related to formulation parameters such as the aggregation state and particle size (11,12).…”