Quaternized Chitosan/Alginate-Fe3O4 Magnetic Nanoparticles Enhance the Chemosensitization of Multidrug-Resistant Gastric Carcinoma by Regulating Cell Autophagy Activity in Mice
Quaternized Chitosan/Alginate-Fe3O4 Magnetic Nanoparticles Enhance the Chemosensitization of Multidrug-Resistant Gastric Carcinoma by Regulating Cell Autophagy Activity in Mice
复制标题
DOI：
10.1166/jbn.2016.2232
复制
发表时间：
2016-05-01
影响因子：
2.9
通讯作者：
Cao, Feng
中科院分区：
文献类型：
--
作者：
Li, Xiujuan;Feng, Jing;Cao, Feng
多药耐药性（MDR）和靶向治疗给肿瘤化疗带来了重大挑战。纳米颗粒（NP）因其在肿瘤靶向细胞毒性和成像方面的优势而有望用于癌症治疗诊断。在这项研究中，我们开发了N-((2-羟基-3-三甲基铵)丙基)氯化壳聚糖(HTCC)/海藻酸盐封装的Fe3O4磁性纳米粒子(HTCC-MNPs)，并将其应用于体内和体外的MDR胃癌。 HTCC-MNPs 采用离子凝胶法由海藻酸钠 (ALG)、Fe3O4 和 HTCC 制备而成。使用动态光散射、透射电子显微镜 (TEM) 和 zeta 电位分析确定纳米颗粒的尺寸和物理特性。 HTCC-MNPs 在耐药癌细胞系 SGC7901/ADR 中表现出优异的水溶性和生物相容性，并显着降低细胞活力，但在正常胃细胞中则没有这种情况（P < 0.05）。 LC3 表达分析表明自噬参与 HTCC-MNP 细胞毒性。此外，使用 DNA 含量测定验证细胞凋亡。与对照组相比，HTCC-MNPs 导致线粒体膜电位损失、ATP 产生减少和活性氧 (ROS) 产生过多 (P < 0.05)。磁共振成像显示荷瘤小鼠体内 HTCC-MNP 富集。体内生物发光成像和肿瘤体积测量表明，HTCC-MNPs 显着抑制体内肿瘤生长（P < 0.05）。总之，HTCC-MNPs 通过诱导细胞自噬和凋亡，显着抑制 MDR 胃肿瘤生长并缩小肿瘤体积，这归因于线粒体功能障碍和过多的 ROS 积累。
Multidrug resistance (MDR) and targeted therapies present major challenges in tumor chemotherapy. Nanoparticles (NPs) hold promise for use in cancer theranostics due to their advantages in terms of tumor-targeted cytotoxicity and imaging. In this study, we developed N-((2-hydroxy-3-trimethylammonium) propyl) chitosan chloride (HTCC)/alginate-encapsulated Fe3O4 magnetic NPs (HTCC-MNPs) and applied them to MDR gastric cancer both in vivo and in vitro. HTCC-MNPs were fabricated from sodium alginate (ALG), Fe3O4 and HTCC using an ionic gelation method. The sizes and, physical characteristics of the NPs were determined using dynamic light scattering, transmission electron microscopy (TEM) and zeta potential analysis. The HTCC-MNPs exhibited excellent water solubility and biocompatibility as well as significantly reduced cell viability in the drug-resistant cancer cell line SGC7901/ADR, but not in normal gastric cells (P < 0.05). An analysis of LC3 expression demonstrated the involvement of autophagy in HTCC-MNP cytotoxicity. Additionally, apoptosis was verified using a DNA content assay. HTCC-MNPs led to mitochondrial membrane potential loss, decreased ATP production and excessive reactive oxygen species (ROS) generation compared to a control group (P < 0.05). Magnetic resonance imaging showed enrichment of HTCC-MNPs in tumor-bearing mice. In vivo bioluminescence imaging and tumor volume measurements revealed that HTCC-MNPs markedly inhibited in vivo tumor growth (P < 0.05). In conclusion, HTCC-MNPs significantly inhibited MDR gastric tumor growth and reduced tumor volume via the induction of cellular autophagy and apoptosis, which was attributed to mitochondrial dysfunction and excessive ROS accumulation.