Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7571, USA.
J Pharm Sci. 2012 Sep;101(9):3292-304. doi: 10.1002/jps.23213. Epub 2012 Jun 6.
Paclitaxel (PTX) is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently, the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection, resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize PTX by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid, which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (≈ 5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor-bearing mice, [(3) H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 h. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23 h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics.
紫杉醇（PTX）是许多癌症的有效化疗药物，但它的溶解度非常差。因此，TAXOL 制剂使用大量的表面活性剂 Cremophor EL 来溶解药物进行注射，导致严重的过敏反应和中性粒细胞减少症。与 Cremophor EL 不同，本文提出了一种通过二羧酸脂肪酸的共轭来溶解 PTX 的方法，该方法可特异性结合无处不在的蛋白质血清白蛋白。共轭化学简化为使用 3-十五烷基戊二酸（PDG）酸的活化酸酐形式的单一步骤，该酸酐形式对各种亲核试剂具有反应性。PDG 衍生物的细胞毒性比母体化合物低，并且发现在血清、肿瘤胞质和肿瘤组织匀浆中缓慢水解为 PTX（≈72 小时内 5%）。当静脉注射到荷瘤小鼠时，TAXOL 制剂中的 [(3) H]-PTX 迅速清除，半衰期为 7 小时。对于 PTX 的 PDG 衍生物，药物迅速分布，约 20%的注射剂量仍留在血管中，半衰期为 23 小时。通过用 PDG 脂肪酸修饰 PTX 可以改善这些特性，为 PDG 成为许多治疗药物的通用修饰剂提供了机会。
