Development of an amphotericin B micellar formulation using cholesterol-conjugated styrene-maleic acid copolymer for enhancement of blood circulation and antifungal selectivity.

Amphotericin B (AmB) is an effective antifungal agent for life-threatening systemic fungal infections. However, its poor solubility in water and organic solvents makes it difficult to formulate. We previously reported AmB-encapsulated micellar formations using styrene-maleic acid copolymer (SMA) and butylated SMA. These micelles make AmB water-soluble; however, the blood circulation of AmB by these intravenous administrations was as low as that of Fungizone®, a conventional micellar formulation of AmB. The destabilization of SMA micelles by salt in the blood has been suggested to be a cause of low blood circulation. Therefore, in this study, to reduce salt-induced instability and increase blood circulation of the micelles, we covalently attached cholesterol molecules to the SMA backbone because AmB interacts with sterols. This AmB nanoparticle micellar formulation (Cho-SMA/AmB micelles) was water-soluble, stable in the presence of salts, and formed a complex with albumin. Compared with Fungizone®, this formulation had equal antifungal activity and markedly improved blood circulation and lower toxicity. Its toxicity was further reduced in the presence of albumin. Taken together, our results indicate that Cho-SMA/AmB micelles could be an intravenous formulation with high antifungal selectivity, and drug interactants-conjugated SMA system could be applied to a variety of drug-loaded nanomicellar systems.