College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, China.
Sci Rep. 2020 Dec 16;10(1):22015. doi: 10.1038/s41598-020-79125-0.
Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. As an attractive component, gold nanoparticles (AuNPs) have been extensively studied as biosafety nanomaterials, but they are rarely explored as drug nanocarriers for targeted co-delivery of multiple chemotherapeutics. Herein, a novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). FUdRs were integrated into DNA hybrid strands decorated on AuNPs by DNA solid phase synthesis, and Dox molecules were intercalated into their duplex regions. Affibody molecules coupled to the DNA hybrid strands were distributed the surface of AuNPs, giving them targeting for HER2. The new dual-drug-containing affibody-DNA-AuNPs (Dox@affi-F/AuNPs) owned compact and stable spherical nanostructures, and precise drug loading. Cytotoxicity tests demonstrated that these nanoparticles caused a higher inhibition in HER2 overexpressing breast cancer cells, and showed better synergistic antitumor activity than simple mixture of the two drugs. The related mechanistic studies proved that Dox@affi-F/AuNPs achieved a remarkable combined antitumor activity of Dox and FUdR by promoting more cells to enter apoptosis pathway. Our work provided a nanomedicine platform for targeted co-delivery of nucleoside analog therapeutics and anthracycline anticancer drugs to achieve synergistic treatment of HER2 cancer.
联合化疗仍然是 HER2 阳性乳腺癌患者标准临床治疗的重要组成部分。作为一种有吸引力的成分，金纳米粒子（AuNPs）已被广泛研究为生物安全纳米材料，但它们很少被探索作为用于靶向共递多种化疗药物的药物纳米载体。在此，我们制备了一种新型的亲和体-DNA 杂合链修饰的 AuNPs，用于共载核苷类似物（5-氟尿嘧啶，FUdR）和蒽环类药物（阿霉素，Dox）。通过 DNA 固相合成将 FUdRs 整合到修饰在 AuNPs 上的 DNA 杂合链中，并且 Dox 分子被插入其双链区域。与 DNA 杂合链偶联的亲和体分子分布在 AuNPs 的表面，赋予它们针对 HER2 的靶向性。新型载双药的亲和体-DNA-AuNPs（Dox@affi-F/AuNPs）具有紧凑且稳定的球形纳米结构和精确的载药能力。细胞毒性试验表明，这些纳米颗粒在过表达 HER2 的乳腺癌细胞中引起更高的抑制作用，并且显示出比两种药物简单混合物更好的协同抗肿瘤活性。相关的机制研究证明，Dox@affi-F/AuNPs 通过促进更多细胞进入凋亡途径，实现了 Dox 和 FUdR 的联合抗肿瘤活性的显著增强。我们的工作为靶向共递核苷类似物治疗剂和蒽环类抗癌药物提供了一种纳米医学平台，以实现针对 HER2 癌症的协同治疗。
