Oliveira Tiago R, Benatti Carlos R, Lamy M Teresa
Universidade de Sao Paulo, Sao Paulo, Brazil.
Biochim Biophys Acta. 2011 Nov;1808(11):2629-37. doi: 10.1016/j.bbamem.2011.07.042. Epub 2011 Aug 3.
Amphotericin B (AmB) is widely used in the treatment of systemic fungal infections, despite its toxic effects. Nephrotoxicity, ascribed as the most serious toxic effect, has been related to the state of aggregation of the antibiotic. In search of the increase in AmB antifungal activity associated with low toxicity, several AmB-amphiphile formulations have been proposed. This work focuses on the structural characterization of a specific AmB formulation: AmB associated with sonicated dioctadecyl dimethylammonium bromide (DODAB) aggregates. Here, it was confirmed that sonicated DODAB dispersion is constituted by DODAB bicelles, and that monomeric AmB is much more soluble in bicelles than in DODAB vesicles. A new optical parameter is proposed for the estimation of the relative amount of amphiphile-bound monomeric AmB. With theoretical simulations of the spectra of spin labels incorporated in DODAB bicelles it was possible to prove that monomeric AmB binds preferentially to lipids located at the edges of DODAB bicelles, rigidifying them, and decreasing the polarity of the region. That special binding of monomeric AmB along the borders of bicelles, where the lipids are highly disorganized, could be used in the formulation of other carriers for the antibiotic, including mixtures of natural lipids which are known to form bicelles.
两性霉素B（AmB）尽管具有毒性作用，但仍广泛用于治疗全身性真菌感染。肾毒性被认为是最严重的毒性作用，与抗生素的聚集状态有关。为了寻找与低毒性相关的AmB抗真菌活性的增加，人们提出了几种AmB-两亲物制剂。这项工作的重点是一种特定的AmB制剂的结构表征：与超声处理的二辛基二甲基溴化铵（DODAB）聚集体相关的AmB。在此，证实了超声处理的DODAB分散体由DODAB双分子层构成，并且单体AmB在双分子层中的溶解度比在DODAB囊泡中高得多。提出了一种新的光学参数来估计两亲物结合的单体AmB的相对量。通过对掺入DODAB双分子层中的自旋标记光谱的理论模拟，有可能证明单体AmB优先与位于DODAB双分子层边缘的脂质结合，使其变硬，并降低该区域的极性。单体AmB沿着双分子层边缘的特殊结合，那里的脂质高度无序，可以用于配制抗生素的其他载体，包括已知能形成双分子层的天然脂质混合物。
