Center for Pharmacogenetics, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
Mol Pharm. 2013 Aug 5;10(8):2880-90. doi: 10.1021/mp300729y. Epub 2013 Jul 11.
Various PEG-Vitamin E conjugates including d-α-tocopheryl poly(ethylene glycol) succinate 1000 (TPGS) have been extensively studied as a nonionic surfactant in various drug delivery systems. However, limited information is available about the structure-activity relationship of PEG-Vitamin E conjugates as a micellar formulation for paclitaxel (PTX). In this study, four PEG-Vitamin E conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/Vitamin E (1/1 vs 1/2) in the conjugates. These conjugates were systematically characterized with respect to CMC, PTX loading efficiency, stability, and their efficiency in delivery of PTX to tumor cells in vitro and in vivo. Our data show that PEG5K-conjugates have lower CMC values and are more effective in PTX loading with respect to both loading capacity and stability. The conjugates with two Vitamin E molecules also worked better than the conjugates with one molecule of Vitamin E, particularly for PEG2K-system. Furthermore, all of the PEG-Vitamin E conjugates can induce significant suppression of P-gp function. More importantly, PTX-loaded PEG5K-VE2 resulted in significantly improved tumor growth inhibitory effect in comparison to PTX formulated in PEG2K-VE or PEG2K-VE2, as well as Cremophor EL (Taxol) in a syngeneic mouse model of breast cancer (4T1.2). Our study suggests that PEG5K-Vitmin E2 may hold promise as an improved micellar formulation for in vivo delivery of anticancer agents such as PTX.
各种聚乙二醇-维生素 E 缀合物，包括 d-α-生育酚聚乙二醇琥珀酸酯 1000（TPGS），已被广泛研究作为各种药物传递系统中的非离子表面活性剂。然而，关于作为紫杉醇（PTX）胶束制剂的聚乙二醇-维生素 E 缀合物的结构-活性关系的信息有限。在这项研究中，开发了四种聚乙二醇-维生素 E 缀合物，它们在聚乙二醇（PEG2K 与 PEG5K）的分子量和缀合物中聚乙二醇/维生素 E 的摩尔比（1/1 与 1/2）方面有所不同。这些缀合物在 CMC、PTX 负载效率、稳定性以及它们在体外和体内将 PTX 递送至肿瘤细胞的效率方面进行了系统表征。我们的数据表明，PEG5K-缀合物具有较低的 CMC 值，并且在 PTX 负载方面更有效，无论是在载药量还是稳定性方面。具有两个维生素 E 分子的缀合物也比具有一个维生素 E 分子的缀合物更有效，特别是对于 PEG2K 系统。此外，所有的聚乙二醇-维生素 E 缀合物都可以诱导 P-糖蛋白功能的显著抑制。更重要的是，与用 PEG2K-VE 或 PEG2K-VE2 以及 Cremophor EL（Taxol）配制的 PTX 相比，负载 PTX 的 PEG5K-VE2 导致在乳腺癌（4T1.2）同基因小鼠模型中肿瘤生长抑制作用显著改善。我们的研究表明，PEG5K-Vitmin E2 可能作为一种改进的胶束制剂，用于体内递送抗癌药物，如 PTX。
