自组装球形氧化铈抑制胃癌细胞增殖和迁移基础研究

Self-Assembled Spherical Cerium Oxide Inhibit Migration and Proliferation of Gastric Cancer

胃癌(gastric cancer,GC)是全球最常见肿瘤相关死亡原因之一,具有极高的潜在转移风险。目前众多治疗方案的效果并不尽人意,亟需探索新的治疗方法。在纳米医学领域,氧化铈纳米颗粒(cerium oxide nanoparticles,CNPs)可通过其氧空位介导的化学反应性显示出抗癌活性。然而,CNPs在胃癌中的实际效果并不明确。因此,通过可控合成球形氧化铈纳米颗粒(spherical cerium oxide nanoparticles,Ceria-SNPs)并对其表征,探讨Ceria-SNPs对人胃癌细胞MKN-45的作用。结果发现,Ceria-SNPs的平均粒径为14 nm,比表面积为59.54 m^(2)·g^(-1)。将不同浓度的Ceria-SNPs与胃癌细胞共培养,并在体外和体内检测细胞增殖和迁移能力。结果发现,高浓度(10.0μg·ml^(-1))的Ceria-SNPs能抑制胃癌细胞的增殖和迁移,且该过程是通过增加细胞内活性氧(reactive oxygen species,ROS)水平实现的;裸鼠皮下成瘤与腹腔转移模型进一步验证效能和生物安全性。Ceria-SNPs可以通过增加细胞内ROS水平抑制胃癌恶性生物学行为,而根据特殊应用需求可控合成CNPs为其进一步开展医用研究提供了材料支撑。

Gastric cancer(GC)has the fifth highest incidence rate and fourth highest mortality rate worldwide,with a highly significant risk of metastasis.Due to the difficulty in detecting early symptoms of gastric cancer and the low rate of gastric endoscopy screening,most patients are already in the advanced stage at the time of diagnosis.Comprehensive treatment is the overall strategy for gastric cancer treatment,with surgery being the main focus,while chemotherapy can improve the survival rate and quality of life for patients with locally advanced unresectable or metastatic gastric cancer.The key to gastric cancer treatment is early detection,diagnosis,and appropriate treatment methods.The treatment efficacy of gastric cancer,however,is still far from satisfactory.With the 5-year survival rate for advanced gastric cancer lingering below 30%,the primary causes of cancer-related fatalities persist as tumor invasion and metastasis.Thus,a pressing necessity emerges for intensive exploration and advancement to enhance the survival rate and therapeutic consequences for patients grappling with gastric cancer,by discovering and employing increasingly efficacious drugs that can effectively stymie the proliferation and migration of gastric cancer cells.Nanotechnology,being a"disruptive technology",has demonstrated immense potential for enhancing numerous disease treatments and diagnoses.With the escalating demand for individualized and accurate drug therapies,there is an escalating interest in the advancement of nano particles.These nano particles have already played diverse therapeutic roles in various diseases including chemotherapy,photodynamic therapy,radiation therapy,and immunotherapy.The continuing advancements in nanotechnology will cater to medical requirements more effectively,offering patients more personalized treatments and more efficient drug delivery systems.Research has found that in the field of nanomedicine,cerium oxide nanoparticles(CNPs)have the potential to be a highly effective treatment method for a wide range of diseases.CNPs have important prospects in the field of biomedical research due to their ability to simulate the activity of important antioxidant enzymes called superoxide anion dismutase(SOD).This unique enzyme activity is attributed to the presence of both Ce^(3+)and Ce^(4+)oxidation states on the surface of CNPs,which creates oxygen vacancies.These oxygen vacancies serve as binding sites for redox reactions and regulate the level of reactive oxygen species(ROS)within cells.ROS are normal byproducts of cellular activities such as mitochondrial metabolism and protein folding.However,when ROS levels are excessively elevated,they have the potential to induce oxidative stress in cells,ultimately leading to the aging or demise of the cell.In contrast to regular cells,cancer cells typically exhibit augmented levels of ROS and heightened antioxidant activity in an unregulated state.Consequently,cancer cells struggle to manage additional oxidative stress and consequently become more vulnerable to attacks from reactive oxygen species.Therefore,augmenting intracellular ROS represents a significant avenue in the development of drugs for cancer treatment.Based on the aforementioned theory,researchers have focused on studying the regulation of cell proliferation by CNPs,and the reports have indicated that the size of CNPs can determine the ratio of Ce^(3+)and Ce^(4+)on their surface.However,ultrasmall CNPs tend to aggregate,resulting in a significant reduction in their bioactivity.Moreover,when it comes to treating gastric cancer,CNPs have not yet displayed sufficiently significant therapeutic effects,which hinder their ability to distinguish themselves among the numerous available treatment options.Therefore,it is crucial to improve the simulated enzyme activity of CNPs.Our research team has previously enhanced the stability and aggregation of CNPs through controlled synthesis techniques,but the anti-tumor characteristics and bio-safety of CNPs still require further exploration.Therefore,this study aimed to investigate the impact of spherical cerium oxide nanoparticles(Ceria-SNPs)on human gastric cancer cells(MKN-45)through the synthesis and characterization of controlled Ceria-SNPs.Different concentrations of Ceria-SNPs were co-cultivated with gastric cancer cells,and the cell proliferation,migration ability,and intracellular ROS levels were evaluated in both in vitro and in vivo conditions.It was discovered that a high concentration of 10.0μg·ml^(-1)of Ceria-SNPs had the ability to hinder the growth and movement of gastric cancer cells,which was achieved by elevating the levels of intracellular ROS.Furthermore,the findings had been validated through experiments using subcutaneous tumor and abdominal metastasis models in nude mice,which confirmed the efficacy and safety of CeriaSNPs.The results strongly suggested that by elevating intracellular ROS levels,Ceria-SNPs could effectively impede the malignant biological behavior of gastric cancer.Moreover,the utilization of controllable synthesis technology provided a theoretical basis for the application of CNPs.In conclusion,it was indicated that Ceria-SNPs could effectively suppress the malignant biological behavior of gastric cancer by increasing intracellular ROS levels,and the application of controllable synthesis technology for cerium oxide nanoparticles had theoretical support.