Synthesis of a Highly Water-Soluble Derivative of Amphotericin B with Attenuated Proinflammatory Activity

Abstract

Amphotericin B (AmB), a well-known polyene antifungal agent displays a marked tendency to self-associate and, as a consequence, exhibits very poor solubility in water. The therapeutic index of AmB is low, and is associated with significant dose-related nephrotoxicity, as well as acute, infusion-related febrile reactions. Reports in the literature indicate that that toxicity of AmB may be related to the physical state of the drug. Reaction of AmB in dimethylformamide with bis(dimethylaminopropyl)carbodiimide yielded an unexpected N-alkylguanidine/N-acylurea bis-adduct of AmB which was highly water soluble. The absorption spectrum of the AmB derivative in water indicated excellent monomerization, and the anti-fungal activities of reference AmB and its water-soluble derivative against C. albicans were found to be virtually identical. Furthermore, the water-soluble adduct is significantly less active in engaging TLR4 which would suggest that the adduct may be less proinflammatory.

Identification of Adjuvantic Activity of Amphotericin B in a Novel, Multiplexed, Poly-TLR/NLR High-Throughput Screen

“…Simultaneous deconvolution and dose-response profiles in individual reporter cell lines (HEK2, HEK3, HEK4, HEK5, HEK7, HEK8, HEK9, NOD1 and HEK-Null) were performed for all provisional hits. AmpB and nystatin showed dose-dependent NF-κB induction in human TLR2- and TLR4-specific reporter cell lines ( Fig 5 ), consistent with previous reports demonstrating TLR2 and TLR4 activation by these antifungal agents [ 81 – 83 ].…”

“…Given the dose-dependent TLR2- and TLR4-agonistic properties [ 81 – 83 ] of AmpB ( Fig 5 ), we compared cytokine and chemokine induction by AmpB to the TLR2-specific diacyl and triacyl lipopeptides PAM 2 CSK 4 and PAM 3 CSK 4 (which signal via TLR2/6 and TLR2/1 heterodimerization, respectively [ 87 , 88 ]), MPLA, a TLR4 agonist which is a component of the FDA-approved AS04 adjuvant [ 18 – 20 ], as well as LPS, a highly proinflammatory TLR4 agonist, in human PBMCs. A high degree of congruence in the pattern of cytokine and chemokine induction between AmpB and MPLA was observed ( Fig 6 ), suggesting a TRIF-biased signaling for AmpB, as has been observed for MPLA [ 89 – 91 ].…”

Estratégias Tecnológicas Para Formulações De Anfotericina B Em Sistemas Lipídicos Disponíveis No Mercado Farmacêutico E Outros Promissores Sistemas De Administração

“…A baixa solubilidade em água e em muitos solventes aquosos constitui um sério problema para a definição de uma forma de administração da AmB. O antifúngico possui tendência de se autoassociar formando dímeros ou trimeros, com maior dificuldade solubilização em água e tampões aquosos (31).…”

Microemulsion based gel for topical dermal delivery of pseudolaric acid B: In vitro and in vivo evaluation

“…Amphotericin B has been the standard 1 Abbreviations AUC, area under the concentration-time curve; C max , peak concentration; HPLC, high performance liquid chromatography; IPM, isopropyl myristate; MD, microdialysis; ME, microemulsion; ME-gel, microemulsion based gel; NS, normal saline; PAB, pseudolaric acid B; PAB ME-gel, pseudolaric acid B microemulsion based gel; PAB gel, pseudolaric acid B hydrogel, PAB ME, pseudolaric acid B microemulsion; PDI, polydispersity index; RR, relative recovery; RL, relative loss; SD, Sprague Dawley; SDA, sabouraud dextrose agar; TEM, transmission electron microscopy; T max , peak time. treatment for candidal infection, however, its severe nephrotoxicity limited its clinical use (Adediran, et al, 2009). Currently, the azole antifungal agents such as miconazole, ketoconazole, fluconazole and itraconazole were considered as the principal drugs in the treatment for candidal infections (Bodey., 1992).…”