Department of Oral Pathology, Faculty of Dentistry, Alexandria University, Egypt.
Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Egypt.
Oral Dis. 2021 Mar;27(2):251-265. doi: 10.1111/odi.13551. Epub 2020 Aug 6.
Gold nanoparticles (AuNPs) are used to deliver drugs and therapeutic small molecule inhibitors to cancer cells. Evidence shows that AuNPs coated with nuclear localization sequence can cross the nuclear membrane and induce cellular apoptosis. To determine the therapeutic role of AuNPs, we compared two nanoconstructs conjugated to doxorubicin (DOX) through pH-sensitive and pH-resistant linkers.
We tested DOX nanoconjugates' cytotoxicity, cellular and nuclear uptake in oral squamous cell carcinoma cell line. Furthermore, we evaluated the therapeutic effect of pH-sensitive and pH-resistant DOX bioconjugates in hamster buccal pouch carcinoma model.
Our data indicate that pH-resistant and pH-sensitive DOX-nanoconjugates were equally localized in cancer cells, but the pH-resistant DOX nanoparticles were more localized in the nuclei inducing a 2-fold increase in the apoptotic effect compared with the pH-sensitive DOX nanoparticles. Our in vivo results show significantly higher tumor shrinkage and survival rates in animals treated with DOX pH-resistant AuNPs compared with pH-sensitive ones.
Our findings suggest that AuNPs enhance the cytotoxic effect against cancer cells in addition to acting as drug carriers. DOX pH-resistant AuNPs enhanced accumulation of AuNPs in cancer cells' nuclei inducing a significant cellular apoptosis which was confirmed using in vitro and in vivo experiments without deleterious effects on blood cell count.
金纳米颗粒（AuNPs）用于将药物和治疗性小分子抑制剂递送到癌细胞中。有证据表明，带有核定位序列的 AuNPs 可以穿过核膜并诱导细胞凋亡。为了确定 AuNPs 的治疗作用，我们比较了两种通过 pH 敏感和 pH 稳定连接子连接到阿霉素（DOX）的纳米结构。
我们测试了 DOX 纳米复合物在口腔鳞状细胞癌细胞系中的细胞毒性、细胞内和核内摄取。此外，我们评估了 pH 敏感和 pH 稳定 DOX 生物缀合物在仓鼠颊囊癌模型中的治疗效果。
我们的数据表明，pH 稳定和 pH 敏感的 DOX-纳米复合物在癌细胞中同样定位，但 pH 稳定的 DOX 纳米颗粒在细胞核中的定位更多，与 pH 敏感的 DOX 纳米颗粒相比，诱导细胞凋亡的效果增加了 2 倍。我们的体内结果表明，与 pH 敏感的 DOX AuNPs 相比，用 DOX pH 稳定的 AuNPs 治疗的动物肿瘤缩小和存活率显著提高。
我们的研究结果表明，AuNPs 除了作为药物载体外，还可以增强对癌细胞的细胞毒性作用。DOX pH 稳定的 AuNPs 增强了 AuNPs 在癌细胞核内的积累，诱导了显著的细胞凋亡，这通过体外和体内实验得到了证实，对血细胞计数没有不良影响。
