COMPARISON OF SOLUTOL HS-15, CREMOPHOR EL AND NOVEL ETHOXYLATED FATTY-ACID SURFACTANTS AS MULTIDRUG-RESISTANCE MODIFICATION AGENTS
COMPARISON OF SOLUTOL HS-15, CREMOPHOR EL AND NOVEL ETHOXYLATED FATTY-ACID SURFACTANTS AS MULTIDRUG-RESISTANCE MODIFICATION AGENTS
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DOI：
10.1002/ijc.2910620413
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发表时间：
1995-08-09
影响因子：
6.4
通讯作者：
COON, JS
中科院分区：
文献类型：
--
作者：
BUCKINGHAM, LE;BALASUBRAMANIAN, M;COON, JS
一些著名的脂肪酸酯表面活性剂，如Cremophor EL和solutool HS 15，是体外和体内多药耐药的调节剂。由于它们是多分散的，而且它们的活性成分尚未被确定，因此这些表面活性剂的治疗潜力尚不清楚。为了更好地确定溶解醇HS 15的有效成分，并制备更有效的表面活性剂多药耐药调节剂，高纯度的C-18脂肪酸以5-200摩尔比与环氧乙烷酯化。出乎意料的是，纯12-羟基硬脂酸的环氧乙烷酯是Solutol HS 15的主要成分，与Solutol HS 15本身或在相同条件下合成的硬脂酸和油酸酯相比，其抗性改性活性可以忽略。由于油酸酯具有良好的活性，因此制备了一系列这些化合物来确定环氧乙烷/脂肪酸的最佳比例。发现最佳比例为20摩尔环氧乙烷：1摩尔脂肪酸，高于或低于最佳比例的产品活性急剧下降。最有效的油酸酯，命名为CRL 1337，在体外促进罗丹明123在多药耐药的KB 8-5-11细胞中积累的效力是solutool HS 15的8.4倍，是Cremophor EL的19倍以上。我们的研究结果表明，表面活性剂的疏水结构域（脂肪酸）的结构及其亲水-亲脂平衡是决定表面活性剂作为逆转剂效力的关键。(C) 1995 Wiley-Liss, Inc。
Some well-known fatty acid ester surfactants, e.g., Cremophor EL and Solutol HS 15, are modulators of multidrug resistance in vitro and in vivo. Because they are polydisperse, and their active component(s) have not been identified, the therapeutic potential of such surfactants is unclear. To better define the active components of Solutol HS 15 and to make more potent surfactant multidrug resistance modulators, highly purified C-18 fatty acids were esterified with ethylene oxide at 5-200 molar ratios. Unexpectedly, ethylene oxide esters of pure 12-hydroxy stearic acid, the major components of Solutol HS 15, displayed negligible resistance modification activity compared with Solutol HS 15 itself or to stearic and oleic acid esters synthesized under identical conditions. Since oleic acid esters appeared to have good activity, a series of these compounds was prepared to determine the optimal ethylene oxide/fatty acid ratio. The optimal ratio was found to be 20 mole ethylene oxide:1 mole fatty acid, with a steep decline in activity for products made with ratios above and below the optimum. The most active oleic acid ester, designated CRL 1337, was 8.4-fold as potent as Solutol HS 15 and over 19-fold as potent as Cremophor EL in promoting rhodamine 123 accumulation in multidrug-resistant KB 8-5-11 cells in vitro. Our results show that the structure of the hydrophobic domain (fatty acid) of surfactants as well as its hydrophile-lipophile balance are critical in determining the potency of surfactants as reversing agents. (C) 1995 Wiley-Liss, Inc.