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Synthesis and evaluation of styrene-maleic acid copolymer conjugated amphotericin B.

Abstract：

:Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because it's 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®, 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®, 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®, 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.

journal_name

Int J Pharm

journal_title

International journal of pharmaceutics

authors

Banshoya K,Kaneo Y,Tanaka T,Yamamoto S,Maeda H

doi

10.1016/j.ijpharm.2019.118719

subject

Has Abstract

pub_date

2019-12-15 00:00:00

pages

118719

eissn

0378-5173

issn

1873-3476

pii

S0378-5173(19)30764-1

journal_volume

572

pub_type

杂志文章

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