Redox-Sensitive Hydroxyethyl Starch-Doxorubicin Conjugate for Tumor Targeted Drug Delivery
Redox-Sensitive Hydroxyethyl Starch-Doxorubicin Conjugate for Tumor Targeted Drug Delivery
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DOI：
10.1021/acsami.6b11932
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发表时间：
2016-11-16
影响因子：
9.5
通讯作者：
Yang, Xiangliang
中科院分区：
文献类型：
--
作者：
Hu, Hang;Li, Yihui;Yang, Xiangliang
阿霉素(DOX)是肿瘤化疗中最有效的抗癌药物之一，但由于其非特异性给药引起的严重副作用，限制了其临床应用。为了减轻DOX的副作用，提高其抗肿瘤效果，成功地制备了一种新型氧化还原敏感型羟乙基淀粉阿霉素结合物HES-SS-DOX，其直径为19.9+/-0.4 nm，可用于肿瘤靶向给药和GSH介导的细胞内药物释放。HES-SS-DOX在细胞外GSH水平(与2 mM相似)下相对稳定，而在细胞内GSH水平(2-10 mM)下释放较快。体外细胞实验证实了HES-SS-DOX具有GSH介导的细胞毒作用。与游离DOX相比，HES-SS-DOX的血浆半衰期延长，肿瘤蓄积增加。因此，在体内抗肿瘤活性研究中，与游离DOX相比，HES-SS-DOX显示出更好的抗肿瘤效果和更低的毒性。氧化还原敏感的HES-SS-DOX被证明是一种很有前途的DOX前药，具有临床应用潜力，可实现肿瘤靶向给药和及时的细胞内药物释放，从而有效、安全地进行肿瘤化疗。
Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 +/- 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (similar to 2 mu M) but released DOX quickly under intracellular GSH level (2-10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity as compared to free DOX in the in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of DOX, with clinical potentials, to achieve tumor targeted drug delivery and timely intracellular drug release for effective and safe cancer chemotherapy.