State Key Laboratory of Physical Chemistry of Solid Surfaces, The Key Laboratory for Chemical Biology of Fujian Province, and Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.
Biomater Sci. 2018 Dec 18;7(1):262-271. doi: 10.1039/c8bm01039k.
Cisplatin (CDDP) and arsenic trioxide (ATO), two representative inorganic anticancer drugs, have been successful in the treatment against several kinds of malignancies. However, combination therapy with these two drugs in clinical application suffers from poor pharmacokinetics, serious side effects, and drug resistance of the tumor. Herein, we report a carrier-free aquo-cisplatin arsenite multidrug nanocomposite loaded with cisplatin and arsenic trioxide prodrugs simultaneously. This nanocomposite achieves a high loading capacity and pH-dependent controlled release of the drugs. Because of these features, this nanocomposite shows better in vitro toxicity against various carcinoma cell lines than either the single drug or free drug combination, promotes the synergistic effect of cisplatin and arsenic trioxide, and significantly inhibits the growth of tumors in vivo. Furthermore, cisplatin and arsenic trioxide in this nanocomposite can realize a coordination of both enhanced DNA damage and DNA repair interference within cisplatin-resistant cells, which results in overcoming the drug resistance effectively. Gene expression profiles demonstrate the reduced expression of proto-oncogenes and DNA damage repair related genes MYC, MET, and MSH2, along with the increase of tumor suppressor genes PTEN, VHL, and FAS after the nanocomposite treatment. This type of multidrug nanocomposite offers an alternative and promising strategy for combination therapy and overcoming drug resistance.
顺铂（CDDP）和三氧化二砷（ATO）是两种代表性的无机抗癌药物，已成功用于治疗多种恶性肿瘤。然而，这两种药物联合应用于临床治疗时存在药代动力学不佳、严重的副作用以及肿瘤耐药性等问题。在这里，我们报告了一种载药无载体的顺铂亚砷酸盐多药纳米复合物，该纳米复合物同时负载顺铂和三氧化二砷前药。该纳米复合物具有高载药量和 pH 依赖性药物控制释放的特点。由于这些特性，该纳米复合物对各种癌细胞系的体外毒性均优于单一药物或游离药物组合，促进了顺铂和三氧化二砷的协同作用，并显著抑制了体内肿瘤的生长。此外，该纳米复合物中的顺铂和三氧化二砷可以实现顺铂耐药细胞中增强的 DNA 损伤和 DNA 修复干扰的协同作用，从而有效克服耐药性。基因表达谱表明，纳米复合物处理后原癌基因和与 DNA 损伤修复相关的基因 MYC、MET 和 MSH2 的表达降低，而肿瘤抑制基因 PTEN、VHL 和 FAS 的表达增加。这种多药纳米复合物为联合治疗和克服耐药性提供了一种替代的、有前途的策略。
