期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 572, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ijpharm.2019.118719
关键词
Styrene-maleic acid copolymer; Amphotericin B; Polymer-drug conjugates; Water soluble; Antifungal selectivity
Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because ifs sparingly soluble in water and organic solvents. We previously prepared AmB-loaded micelles using styrene-maleic acid copolymer (SMA). Although solubilization was achieved by this formulation, stability in the blood circulation was as insufficient as that of Fungizone (R), which is a conventional formulation of AmB. Meanwhile, it is well known that polymer-drug conjugates are more stable in circulation than drug-loaded micelles. Therefore, in this study, we developed covalently conjugated SMA-AmB (SMA-AmB conjugate). The SMA-AmB conjugate was found to be soluble and present as micelles in aqueous solution. Furthermore, it was revealed that this micelle behaves as a larger molecule by forming a complex with albumin. The circulation in the blood increased significantly compared to that of Fungizone (R), which was suggested to be due to this complex-forming ability. Although in vitro and in vivo antifungal activity of the SMA-AmB conjugate against Saccharomyces cerevisiae was reduced by 1/3 compared to that of Fungizone (R), hemolysis decreased to 1/40 or less, and the LD50 decreased to 1/10. In conclusion, it is expected that the SMA-AmB conjugate can be a polymer-therapeutic agent with high antifungal selectivity.
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