Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro.
Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro.
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DOI：
10.1016/j.jconrel.2011.01.024
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发表时间：
2011-05-30
期刊：
影响因子：
--
通讯作者：
Zhang M
中科院分区：
文献类型：
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作者：
Kievit FM;Wang FY;Fang C;Mok H;Wang K;Silber JR;Ellenbogen RG;Zhang M
多药耐药性 (MDR) 的特点是 ATP 结合盒 (ABC) 转运蛋白的过度表达，这些转运蛋白会主动将多种疏水性化疗药物从癌细胞中泵出。 MDR 是多种人类肿瘤治疗耐药的主要机制，临床上适用的规避 MDR 的策略仍有待确定。在这里，我们描述了一种旨在规避 MDR 的载药氧化铁纳米颗粒的制造和表征。阿霉素 (DOX) 是一种常用于癌症化疗的蒽环类抗生素，也是 ABC 介导的药物流出的底物，通过 pH 敏感的腙键与聚乙烯亚胺共价结合，并与涂有胺封端聚乙二醇的氧化铁纳米颗粒缀合。体外评估了 DOX-腙键的载药量、理化性质和 pH 不稳定性。在野生型和 DOX 抗性 ABC 转运蛋白过表达的大鼠神经胶质瘤 C6 细胞中，比较了纳米颗粒的摄取、保留和对活力的剂量依赖性影响。我们发现，在酸性 pH 条件下，纳米颗粒释放的 DOX 最大，表明腙键断裂。 DOX 结合的纳米颗粒很容易被野生型和耐药细胞吸收。与游离药物相比，DOX 缀合的纳米颗粒在耐药细胞中持续存在，表明它们不受药物外流的影响。与用游离药物处理的细胞相比，DOX 缀合纳米颗粒的更大保留伴随着活力的降低。我们的结果表明，DOX 结合的纳米颗粒可以通过规避 MDR 来提高化疗的疗效。
Multidrug resistance (MDR) is characterized by the overexpression of ATP-binding cassette (ABC) transporters that actively pump a broad class of hydrophobic chemotherapeutic drugs out of cancer cells. MDR is a major mechanism of treatment resistance in a variety of human tumors, and clinically applicable strategies to circumvent MDR remain to be characterized. Here we describe the fabrication and characterization of a drug-loaded iron oxide nanoparticle designed to circumvent MDR. Doxorubicin (DOX), an anthracycline antibiotic commonly used in cancer chemotherapy and substrate for ABC-mediated drug efflux, was covalently bound to polyethylenimine via a pH sensitive hydrazone linkage and conjugated to an iron oxide nanoparticle coated with amine terminated polyethylene glycol. Drug loading, physiochemical properties and pH lability of the DOX-hydrazone linkage were evaluated in vitro. Nanoparticle uptake, retention, and dose-dependent effects on viability were compared in wild-type and DOX-resistant ABC transporter over-expressing rat glioma C6 cells. We found that DOX release from nanoparticles was greatest at acidic pH, indicative of cleavage of the hydrazone linkage. DOX-conjugated nanoparticles were readily taken up by wild-type and drug-resistant cells. In contrast to free drug, DOX-conjugated nanoparticles persisted in drug-resistant cells, indicating that they were not subject to drug efflux. Greater retention of DOX-conjugated nanoparticles was accompanied by reduction of viability relative to cells treated with free drug. Our results suggest that DOX-conjugated nanoparticles could improve the efficacy of chemotherapy by circumventing MDR.