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一种破坏二硫酸结合物的β-环氧德素配方,用于改善全身暴露

Zaafir M Dulloo¹, Ion Ghiviriga¹, Mary E Law²

¹Department of Chemistry, University of Florida PO BOX 117200 Gainesville FL 32611-7200 USA castellano@chem.ufl.edu.

RSC medicinal chemistry

|June 2, 2025

概括

环氧增强了用于乳腺癌治疗的二硫化键破坏剂 (DDAs) 的口服输送. 配制DDAs与环极素改善了溶解性和药理动力学,保持了抗癌活性.

科学领域:

药用化学医学化学
药物运输药物运输药物运输
药理学药理学是指药理学的学科.

背景情况:

双硫化键破坏剂 (DDAs) 选择性地向HER家族过度表达的乳腺癌细胞.
增加DDAs的脂性与功效相关,但由于溶解性差,口服给药具有挑战.
环极素 (CDs) 作为辅助剂被探索以改善脂性药物的可溶性和输送.

研究的目的:

为了研究一种强大的DDA,tcyDTDO的配方,与β-cyclodextrin (BCD) 和2-hydroxypropyl-beta-cyclodextrin (HPB).
评估循环德林复合对tcyDTDO可溶性,抗癌活性和药物动力学特征的影响.
为了确定环极素结合亲和力和DDAs的体内药理动力学之间的相关性.

主要方法:

在 silico 方法 (主体腔体积,结合能量的计算) 指导了 BCD 的选择.
固态纳入复合物 (ICs) 通过制制备,并使用ATR-FTIR和NMR光谱学进行表征.
阶段溶解性研究确定了复杂的固态度和结合常量 (K_a);进行了体外细胞毒性和大鼠药理学研究.

主要成果:

BCD与tcyDTDO形成了一个更强的复合物 (K_a = 4090 M^-1),从而使溶解度增加了3倍.
HPB 呈现较低的亲和力 (K_a = 81 M^-1),但可溶性提高了 90 倍.
两种BCD和HPB配方在MDA-MB-468细胞中保持了体外细胞毒性;BCD配方在老鼠中显示出优异的药物动力学特征 (AUC0-24 = 3150 ± 381 ng h mL-1).

结论:

循环德克斯林复合有效地提高了像tcyDTDO这样的脂性DDA的溶解度.
BCD复杂化显著改善了tcyDTDO的体内药动力学特征和全身暴露.
这项研究提出了口服DDAs的可行策略,将结合 afinity 与药理动力学结果相关联.

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