Nanotechnology Program, School of Sciences & Engineering , The American University in Cairo (AUC) , New Cairo 11835 , Egypt.
Department of Biochemistry, Faculty of Science , Alexandria University , Alexandria 21511 , Egypt.
ACS Appl Mater Interfaces. 2019 Jul 31;11(30):26731-26744. doi: 10.1021/acsami.9b10164. Epub 2019 Jul 16.
Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice ( < 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.
在此，我们将协同药物组合的两种策略与双重主动肿瘤靶向相结合，以有效治疗肝细胞癌 (HCC)。因此，基于肿瘤敏化作用，将天然黄酮类化合物槲皮素 (QRC) 与靶向治疗药物索拉非尼 (SFB) 共同递送至通过蛋白壳-油核纳米胶囊 (NCs) 预形成的磷脂复合物中。受乳铁蛋白 (LF) 通过与 HCC 细胞过度表达的 LF 受体结合的靶向作用的启发，LF 壳通过静电沉积到载药油核上，以阐述 LF 壳-油核 NCs。为了双重肿瘤靶向，将乳糖酸 (LA) 或甘草次酸 (GA) 分别偶联到 LF 壳上，分别与肝癌细胞上的糖蛋白和 GA 受体结合。与 LF 和 GA/LF-NCs 相比，双重靶向 LA/LF-NCs 在 48 h 后与游离联合治疗相比，对 HepG2 细胞的内化率更高，半最大抑制浓度降低了 2 倍。此外，双重靶向 LF-NCs 显示出强大的体内抗肿瘤功效。结果表明，双重靶向 LF-NCs 可显著下调二乙基亚硝胺 (DEN)-诱导的 HCC 小鼠中核因子-κB 和肿瘤坏死因子-α 的 mRNA 表达水平（ < 0.05）。此外，双重靶向 LF-NCs 可减轻 DEN 诱导的动物模型中的肝毒性。总体而言，本研究提出了双重靶向 LF-NCs，用于联合递送 SFB 和 QRC，作为一种有潜力的治疗 HCC 的策略。
