Doxorubicin conjugated to D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS):: Conjugation chemistry, characterization, in vitro and in vivo evaluation
Doxorubicin conjugated to D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS):: Conjugation chemistry, characterization, in vitro and in vivo evaluation
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DOI：
10.1016/j.biomaterials.2008.05.016
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发表时间：
2008-10-01
期刊：
影响因子：
14
通讯作者：
Feng, Si-Shen
中科院分区：
文献类型：
--
作者：
Cao, Na;Feng, Si-Shen
采用d -a-生育酚聚乙二醇1000琥珀酸酯（TPGS）作为多柔比星（DOX）的载体，提高其治疗效果，减少其副作用，制备聚合物-抗癌药物偶联物。阿霉素与TPGS化学偶联。表征了该缀合物的分子结构、载药效率、药物释放动力学和稳定性。以MCF-7乳腺癌细胞和C6胶质瘤细胞为体外细胞模型，研究细胞摄取、细胞内分布和细胞毒性。该偶联物具有较高的细胞摄取效率和更广泛的细胞内分布。经IC50检测，培养24、48、72 h后，结合物对MCF-7细胞的作用分别比母体药物高31.8、69.6、84.1%，对C6细胞的作用分别比母体药物高43.9、87.7、42.2%。以5 mg DOX/kg体重静脉给药后，研究了大鼠体内药代动力学和生物分布。令人欣慰的是，与游离DOX相比，TPGS-DOX偶联物的半衰期增加了4.5倍，曲线下面积（AUC）增加了24倍，心脏、胃和肠中的药物水平显著降低，这表明副作用减少。我们的TPGS-DOX偶联物显示出比DOX本身具有更高治疗效果和更少副作用的前药的巨大潜力。(c) 2008 Elsevier Ltd.版权所有。
To develop a polymer-anticancer drug conjugate, D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) was employed as a carrier of doxorubicin (DOX) to enhance its therapeutic effects and reduce its side effects. Doxorubicin was chemically conjugated to TPGS. The molecular structure, drug loading efficiency, drug release kinetics and stability of the conjugate were characterized. The cellular uptake, intracellular distribution, and cytotoxicity were accessed by using MCF-7 breast cancer cells and C6 glioma cells as in vitro cell model. The conjugate showed higher cellular uptake efficiency and broader distribution within the cells.Judged by IC50, the conjugate was found 31.8, 69.6, 84.1% more effective with MCF-7 cells and 43.9, 87.7, 42.2% more effective with C6 cells than the parent drug after 24, 48, 72 h culture, respectively. The in vivo pharmacokinetics and biodistribution were investigated after an i.v. administration at 5 mg DOX/kg body weight in rats. Promisingly, 4.5-fold increase in the half-life and 24-fold increase in the area-under-the-curve (AUC) of DOX were achieved for the TPGS-DOX conjugate compared with the free DOX The drug level in heart, gastric and intestine was significantly reduced, which is an indication of reduced side effects. Our TPGS-DOX conjugate showed great potential to be a prodrug of higher therapeutic effects and fewer side effects than DOX itself. (c) 2008 Elsevier Ltd. All rights reserved.