Long-Circulating Amphiphilic Doxorubicin for Tumor Mitochondria-Specific Targeting
Long-Circulating Amphiphilic Doxorubicin for Tumor Mitochondria-Specific Targeting
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DOI：
10.1021/acsami.8b17399
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发表时间：
2018-12-19
影响因子：
9.5
通讯作者：
Liu, Haipeng
中科院分区：
文献类型：
--
作者：
Xi, Jingchao;Li, Meng;Liu, Haipeng
线粒体已成为癌症化疗的新靶点，主要是因为它们在能量代谢和细胞凋亡调节中发挥着核心作用。在这里，我们报告了一种新的分子方法，可以实现抗癌药物阿霉素的高水平肿瘤和线粒体选择性递送。这是通过分子工程实现的，分子工程将阿霉素与促溶解聚乙二醇聚合物（两亲性阿霉素或 amph-DOX）缀合的疏水性脂质尾部进行功能化。在体内，与多柔比星缀合的两亲物表现出双重功能：（i）它与血清白蛋白强烈结合并劫持白蛋白的循环和运输途径，导致血液循环延长，增加在肿瘤中的积累，并减少对心脏的暴露； (ii) 它还通过改变药物分子的细胞内分选和运输路线将阿霉素重定向至线粒体。使用 amph-DOX 有效靶向线粒体会导致肿瘤细胞中活性氧水平显着增加，从而比未修饰的阿霉素显着提高抗肿瘤功效。两亲修饰提供了一种简单的策略，可以同时提高阿霉素在癌症化疗中的功效和安全性。
The mitochondria have emerged as a novel target for cancer chemotherapy primarily due to their central roles in energy metabolism and apoptosis regulation. Here, we report a new molecular approach to achieve high levels of tumor- and mitochondria-selective deliveries of the anticancer drug doxorubicin. This is achieved by molecular engineering, which functionalizes doxorubicin with a hydrophobic lipid tail conjugated by a solubility-promoting poly(ethylene glycol) polymer (amphiphilic doxorubicin or amph-DOX). In vivo, the amphiphile conjugated to doxorubicin exhibits a dual function: (i) it binds avidly to serum albumin and hijacks albumin's circulating and transporting pathways, resulting in prolonged circulation in blood, increased accumulation in tumor, and reduced exposure to the heart; (ii) it also redirects doxorubicin to mitochondria by altering the drug molecule's intracellular sorting and transportation routes. Efficient mitochondrial targeting with amph-DOX causes a significant increase of reactive oxygen species levels in tumor cells, resulting in markedly improved antitumor efficacy than the unmodified doxorubicin. Amphiphilic modification provides a simple strategy to simultaneously increase the efficacy and safety of doxorubicin in cancer chemotherapy.