Wang Qiang-Song, Gao Li-Na, Zhu Xiao-Ning, Zhang Yan, Zhang Chuang-Nian, Xu Dong, Cui Yuan-Lu
Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, PR China.
Tianjin State Key Laboratory of Modern Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, PR China.
Theranostics. 2019 Aug 14;9(21):6239-6255. doi: 10.7150/thno.35972. eCollection 2019.
Nanocarrier drug delivery systems (NDDS) have been paid more attention over conventional drug delivery system for cancer therapy. However, the efficacy is hampered by the fast clearance of activated macrophage from the blood circulation system. In this study, glycyrrhizin (GL) was introduced into alginate (ALG) nanogel particles (NGPs) to construct multifunctional delivery vehicle to decrease the fast clearance of activated macrophage and enhance the anticancer efficacy with the combination therapy of GL and doxorubicin (DOX). : We firstly synthesized the GL-ALG NGPs with intermolecular hydrogen bond and ionic bond as the multifunctional delivery vehicle. The immune response and phagocytosis of macrophage on GL-ALG NGPs were investigated on RAW 264.7 macrophages. The pharmacokinetic study of DOX loaded in GL-ALG NGPs was performed in rats. The active targeting effects of GL-ALG NGPs were further studied on hepatocellular carcinoma cell (HepG2) and H22 tumor-bearing mice. Moreover, the anticancer molecular mechanism of DOX/GL-ALG NGPs was investigated on HepG2 cells and tumor-bearing mice . : GL-ALG NGPs could not only avoid triggering the immuno-inflammatory responses of macrophages but also decreasing the phagocytosis of macrophage. The bioavailability of DOX was increased about 13.2 times by DOX/GL-ALG NGPs than free DOX in blood. The mice with normal immune functions used in constructing the tumor-bearing mice instead of the nude mouse also indicated the good biocompatibility of NGPs. GL-mediated ALG NGPs exhibited excellent hepatocellular carcinoma targeting effect and . The results suggested that the anticancer molecular mechanism of the combination therapy of glycyrrhizin and doxorubicin in ALG NGPs was performed via regulating apoptosis pathway of Bax/Bcl-2 ratio and caspase-3 activity, which was also verified in H22 tumor-bearing mice. : DOX/GL-ALG NGPs could attenuate the activation of macrophage and enhance the therapeutic efficacy for hepatocellular carcinoma. Our results suggest that the combination therapy would provide a new strategy for liver cancer treatment.
纳米载体药物递送系统（NDDS）在癌症治疗方面比传统药物递送系统受到了更多关注。然而，活化巨噬细胞从血液循环系统中的快速清除阻碍了其疗效。在本研究中，将甘草酸（GL）引入海藻酸钠（ALG）纳米凝胶颗粒（NGP）中构建多功能递送载体，以减少活化巨噬细胞的快速清除，并通过GL与阿霉素（DOX）的联合治疗提高抗癌疗效。：我们首先合成了具有分子间氢键和离子键的GL-ALG NGP作为多功能递送载体。在RAW 264.7巨噬细胞上研究了巨噬细胞对GL-ALG NGP的免疫反应和吞噬作用。在大鼠中进行了负载于GL-ALG NGP中的DOX的药代动力学研究。进一步在肝癌细胞（HepG2）和荷H22肿瘤小鼠上研究了GL-ALG NGP的主动靶向作用。此外，在HepG2细胞和荷瘤小鼠上研究了DOX/GL-ALG NGP的抗癌分子机制。：GL-ALG NGP不仅可以避免触发巨噬细胞的免疫炎症反应，还可以减少巨噬细胞的吞噬作用。DOX/GL-ALG NGP使DOX在血液中的生物利用度比游离DOX提高了约13.2倍。用于构建荷瘤小鼠的具有正常免疫功能的小鼠而非裸鼠也表明了NGP具有良好的生物相容性。GL介导的ALG NGP表现出优异的肝癌靶向作用。结果表明，甘草酸和阿霉素在ALG NGP中的联合治疗的抗癌分子机制是通过调节Bax/Bcl-2比值和caspase-3活性的凋亡途径来实现的，这在荷H22肿瘤小鼠中也得到了验证。：DOX/GL-ALG NGP可以减弱巨噬细胞的活化并提高肝癌的治疗效果。我们的结果表明，联合治疗将为肝癌治疗提供一种新策略。
