Lei Xiaoying, Li Ke, Liu Yan, Wang Zhen Yu, Ruan Ban Jun, Wang Li, Xiang An, Wu Daocheng, Lu Zifan
State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University.
Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi.
Int J Nanomedicine. 2017 Aug 8;12:5701-5715. doi: 10.2147/IJN.S135849. eCollection 2017.
A combination administration of chemical agents was highlighted to treat tumors. Recently, tumor cell has been found to be different from normal cell in metabolic manner. Most of cancer cells prefer aerobic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) to satisfy energy and biomass synthesis requirement to survive, grow and proliferate, which provides novel and potential therapeutic targets for chemotherapy. Here, 2-deoxy-d-glucose (2-DG), a potent inhibitor of glucose metabolism, was used to inhibit glycolysis of tumor cells; α-tocopheryl succinate (α-TOS), a water-insoluble vitamin E derivative, was chosen to suppress OXPHOS. Our data demonstrated that the combination treatment of 2-DG and α-TOS could significantly promote the anti-tumor efficiency in vitro compared with administration of the single drug. In order to maximize therapeutic activity and minimize negative side effects, a co-delivery nanocarrier targeting folate receptor (FR) was developed to encapsulate 2-DG and α-TOS simultaneously based on our previous work. Transmission electron microscope, dynamic light scattering method and UV-visible spectrophotometers were used to investigate morphology, size distribution and loading efficiency of the α-TOS-2-DG-loaded and FR-targeted nanoparticles (TDF NPs). The TDF NPs were found to possess a layer-by-layer shape, and the dynamic size was <100 nm. The final encapsulation efficiencies of α-TOS and 2-DG in TDF NPs were 94.3%±1.3% and 61.7%±7.7% with respect to drug-loading capacities of 8.9%±0.8% and 13.2%±2.6%, respectively. Almost no α-TOS release was found within 80 h, and release of 2-DG was sustained and slow within 72 h. The results of FR binding assay and fluorescence biodistribution revealed that TDF NPs could target FR highly expressed on tumor cell in vitro and in vivo. Further, in vivo anti-tumor experiments showed that TDF NPs had an improved biological function with less toxicity. Thus, our work indicates that the co-delivery TDF NPs have a great potential in tumor therapy.
强调了化学药物联合给药用于治疗肿瘤。最近，人们发现肿瘤细胞在代谢方式上与正常细胞不同。大多数癌细胞更喜欢有氧糖酵解而非线粒体氧化磷酸化（OXPHOS），以满足能量和生物量合成需求，从而存活、生长和增殖，这为化疗提供了新的潜在治疗靶点。在此，2-脱氧-D-葡萄糖（2-DG），一种有效的葡萄糖代谢抑制剂，被用于抑制肿瘤细胞的糖酵解；α-生育酚琥珀酸酯（α-TOS），一种水不溶性维生素E衍生物，被选来抑制OXPHOS。我们的数据表明，与单药给药相比，2-DG和α-TOS联合治疗在体外可显著提高抗肿瘤效率。为了使治疗活性最大化并将负面副作用最小化，基于我们之前的工作，开发了一种靶向叶酸受体（FR）的共递送纳米载体，以同时包封2-DG和α-TOS。使用透射电子显微镜、动态光散射法和紫外可见分光光度计来研究负载α-TOS-2-DG且靶向FR的纳米颗粒（TDF NPs）的形态、尺寸分布和负载效率。发现TDF NPs具有层层结构，动态尺寸小于100 nm。就载药量分别为8.9%±0.8%和13.2%±2.6%而言，TDF NPs中α-TOS和2-DG的最终包封效率分别为94.3%±1.3%和61.7%±7.7%。在80小时内几乎未发现α-TOS释放，2-DG在72小时内的释放持续且缓慢。FR结合试验和荧光生物分布结果表明，TDF NPs在体外和体内均可高度靶向肿瘤细胞上高表达的FR。此外，体内抗肿瘤实验表明，TDF NPs具有改善的生物学功能且毒性较小。因此，我们的工作表明共递送TDF NPs在肿瘤治疗中具有巨大潜力。
