Zhang Xiaolan, Huang Yixian, Zhao Wenchen, Chen Yichao, Zhang Peng, Li Jiang, Venkataramanan Raman, Li Song
Center for Pharmacogenetics, ‡Department of Pharmaceutical Sciences, School of Pharmacy, and §University of Pittsburgh Cancer Institute, University of Pittsburgh , Pittsburgh, Pennsylvania 15261, United States.
Mol Pharm. 2014 Aug 4;11(8):2807-14. doi: 10.1021/mp500181x. Epub 2014 Jul 11.
We have recently designed and developed a dual-functional drug carrier that is based on poly(ethylene glycol) (PEG)-derivatized farnesylthiosalicylate (FTS, a nontoxic Ras antagonist). PEG5K-FTS2 readily form micelles (20-30 nm) and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these micelles. PTX formulated in PEG5K-FTS2 micelles showed an antitumor activity that was more efficacious than Taxol in a syngeneic mouse model of breast cancer (4T1.2). In order to further improve our PEG-FTS micellar system, four PEG-FTS conjugates were developed that vary in the molecular weight of PEG (PEG2K vs PEG5K) and the molar ratio of PEG/FTS (1/2 vs 1/4) in the conjugates. These conjugates were characterized including CMC, drug loading capacity, stability, and their efficacy in delivery of anticancer drug PTX to tumor cells in vitro and in vivo. Our data showed that the conjugates with four FTS molecules were more effective than the conjugates with two molecules of FTS and that FTS conjugates with PEG5K were more effective than the counterparts with PEG2K in forming stable mixed micelles. PTX formulated in PEG5K-FTS4 micelles was the most effective formulation in inhibiting the tumor growth in vivo.
我们最近设计并开发了一种基于聚乙二醇（PEG）衍生的法尼基硫代水杨酸酯（FTS，一种无毒的Ras拮抗剂）的双功能药物载体。PEG5K-FTS2很容易形成胶束（20 - 30纳米），疏水性药物如紫杉醇（PTX）可以有效地负载到这些胶束中。在同基因乳腺癌小鼠模型（4T1.2）中，用PEG5K-FTS2胶束配制的PTX显示出比紫杉醇更有效的抗肿瘤活性。为了进一步改进我们的PEG-FTS胶束系统，我们开发了四种PEG-FTS缀合物，它们在PEG的分子量（PEG2K与PEG5K）以及缀合物中PEG/FTS的摩尔比（1/2与1/4）方面有所不同。对这些缀合物进行了表征，包括临界胶束浓度、载药能力、稳定性以及它们在体外和体内将抗癌药物PTX递送至肿瘤细胞的功效。我们的数据表明，含有四个FTS分子的缀合物比含有两个FTS分子的缀合物更有效，并且含有PEG5K的FTS缀合物在形成稳定的混合胶束方面比含有PEG2K的对应物更有效。用PEG5K-FTS4胶束配制的PTX是体内抑制肿瘤生长最有效的制剂。
