Luo Shiying, Gu Ying, Zhang Yuannian, Guo Pei, Mukerabigwi Jean Felix, Liu Min, Lei Shaojun, Cao Yu, He Hongxuan, Huang Xueying
†Key Laboratory of Pesticide and Chemical Biology (Ministry of Education), College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
§Prenatal Diagnosis Center, Lianyungang Maternal and Child Hospital, Lianyungang, 222002, P. R. China.
Mol Pharm. 2015 Jul 6;12(7):2318-27. doi: 10.1021/mp500867g. Epub 2015 Jun 16.
A major challenge of combinatorial therapy is the unification of the pharmacokinetics and cellular uptake of various drug molecules with precise control of the dosage thereby maximizing the combined effects. To realize ratiometric delivery and synchronized release of different drugs from a single carrier, a novel approach was designed in this study to load dual drugs onto the macromolecular carrier with different molar ratio by covalently preconjugating dual drugs through peptide linkers to form drug conjugates. In contrast to loading individual types of drugs separately, these drug conjugates enable the loading of dual drugs onto the same carrier in a precisely controllable manner to reverse multidrug resistance (MDR) of human hepatoma (HepG2) cells. As a proof of concept, the synthesis and characterization of xyloglucan-mitomycin C/doxorubicin (XG-MMC/DOX) conjugates were demonstrated. This approach enabled MMC and DOX to be conjugated to the same polymeric carrier with precise control of drug dosage. The cytotoxicity and combinatorial effects were significantly improved compared to the cocktail mixtures of XG-MMC and XG-DOX as well as the individual conjugate of the mixture. Moreover, the results also showed that there was an optimum ratio of dual drugs showing the best cytotoxicity effect and greatest synergy among other tested polymeric conjugate formulations.
联合治疗的一个主要挑战是统一各种药物分子的药代动力学和细胞摄取，并精确控制剂量，从而使联合效应最大化。为了实现从单一载体中不同药物的比例递送和同步释放，本研究设计了一种新方法，通过肽接头将两种药物共价预共轭形成药物偶联物，以不同摩尔比将两种药物负载到高分子载体上。与分别加载单一类型的药物不同，这些药物偶联物能够以精确可控的方式将两种药物加载到同一载体上，以逆转人肝癌（HepG2）细胞的多药耐药性（MDR）。作为概念验证，展示了木葡聚糖-丝裂霉素C/阿霉素（XG-MMC/DOX）偶联物的合成与表征。这种方法能够在精确控制药物剂量的情况下，将MMC和DOX共轭到同一聚合物载体上。与XG-MMC和XG-DOX的混合鸡尾酒以及混合物的单一共轭物相比，细胞毒性和联合效应显著提高。此外，结果还表明，在其他测试的聚合物共轭物配方中，存在一个最佳的双药比例，显示出最佳的细胞毒性效应和最大的协同作用。
