Yu B G, Okano T, Kataoka K, Sardari S, Kwon G S
425 N. Charter Street, School of Pharmacy, University of Wisconsin, Madison, WI 53706-1515, USA.
J Control Release. 1998 Dec 4;56(1-3):285-91. doi: 10.1016/s0168-3659(98)00095-9.
Amphotericin B (AmB) is a membrane-active drug used frequently for the treatment of systemic fungal diseases. Limitations for the use of AmB include poor water solubility and potential for serious systemic toxicities. Recently, it has been demonstrated that the aggregation state of AmB is a determinant factor for toxicity. To increase its therapeutic index, AmB has been solubilized in micelles based on poly(ethylene oxide)-block-poly(beta-benzyl-l-aspartate) (PEO-block-PBLA), using a dialysis method of drug loading. The aggregation state of AmB has been investigated by electronic absorption spectroscopy. AmB loaded in PEO-block-PBLA micelles is non-hemolytic for concentrations up to 15 microgram/ml. AmB as Fungizone(R) initiates hemolysis at 1.0 microgram/ml. The onset of hemolysis correlates with the respective critical aggregation concentrations (CACs) of AmB. The antifungal activity of the AmB-loaded PEO-block-PBLA micelles is four to eight times higher than Fungizone(R) in terms of minimal inhibitory concentrations (MICs). PEO-block-PBLA has no antifungal activity for concentrations up to 200 microgram/ml. The basis for the increase in antifungal activity of AmB-loaded PEO-block-PBLA micelles is unclear, but may be related to a stabilizing effect of the polymeric micelles against auto-oxidation of the AmB heptaene moiety or alternatively, an enhancement in membrane perturbation of fungal cells.
两性霉素B（AmB）是一种常用于治疗全身性真菌疾病的膜活性药物。AmB使用的局限性包括水溶性差和存在严重全身毒性的可能性。最近，已证明AmB的聚集状态是毒性的决定因素。为了提高其治疗指数，采用药物负载的透析方法，将AmB溶解于基于聚环氧乙烷-嵌段-聚（β-苄基-L-天冬氨酸）（PEO-嵌段-PBLA）的胶束中。通过电子吸收光谱法研究了AmB的聚集状态。负载于PEO-嵌段-PBLA胶束中的AmB在浓度高达15微克/毫升时无溶血作用。作为Fungizone®的AmB在1.0微克/毫升时引发溶血。溶血的发生与AmB各自的临界聚集浓度（CACs）相关。就最小抑菌浓度（MICs）而言，负载AmB的PEO-嵌段-PBLA胶束的抗真菌活性比Fungizone®高4至8倍。PEO-嵌段-PBLA在浓度高达200微克/毫升时无抗真菌活性。负载AmB的PEO-嵌段-PBLA胶束抗真菌活性增加的原因尚不清楚，但可能与聚合物胶束对AmB七烯部分自氧化的稳定作用有关，或者与真菌细胞膜扰动的增强有关。
