The Study Of Silicon Dioxide Drug-Carrier System On Inhibiting Squamous Cell Carcinoma Of Head And Neck By Enhancing Intracellular Oxidative Stress

Background:Squamous cell carcinoma of the head and neck(HNSCC)is one of the most common tumors and the sixth highest incidence of cancer worldwide.It has the characteristics of high proliferation,local lymph node metastasis,poor prognosis,etc.Surgical treatment was adopted in the early stage,while platinum-based comprehensive sequence therapy was adopted in the late stage.Cisplatin(CDDP)is one of the most commonly used chemotherapeutic agents for HNSCC.It combines with RNA,DNA and protein to form different types of adducts,thus destroying its structure.Inducing the formation of mitochondrial dependent reactive oxygen species(ROS),resulting in intracellular redox imbalance.The intracellular glutathione(GSH)alleviates the intracellular redox imbalance and increases the resistance of cancer cells to cisplatin,thereby limiting the clinical applicability of CDDP as an anticancer therapy.Therefore,amplifying intracellular oxidative stress by consuming intracellular glutathione to destroy the redox balance is an effective method for the treatment of cancer.Purpose:The maintenance of redox balance by GSH in cancer cells is one of the important reasons for the increased resistance of cancer cells to cisplatin,so the chemotherapy effect of cisplatin on HNSCC can be enhanced by inhibiting the synthesis of GSH.In this paper,a hyaluronic acid(HA)-coated mesoporous silicon dioxide(MS)nanocarrier system was proposed for the co-delivery of L-Butylmethionine Sulfoxide Amine(BSO)and cisplatin prodrug(DSCP)(defined as Pt/BSO-MS-HA).To explore the therapeutic effect of this system on squamous cell carcinoma of head and neck.Methods:1.A synthetic nano-drug loading system Pt/BSO-MS-HA was constructed,and the material properties of Pt/BSO-MS-HA,such as particle size,morphology,drug release and cisplatin loading rate,were tested.2.The experiment of Pt/BSO-MS-HA in vitro:(1).The cytotoxicity of Pt,Pt/BSO,Pt/BSO-MS and Pt/BSO-MS-HA was determined by using the CAL-27 cell line and the MTT assay.(2).To study the uptake of Pt/BSO-MS and Pt/BSO-MS-HA in CAL-27 cells by flow cytometry and confocal microscopy imaging analysis.(3).Detection of intracellular ROS level.(4).Detection of intracellular GSH level.3.The experiment of Pt/BSO-MS-HA in vivo:(1).A tumor-bearing mouse model was constructed using CAL-27 cell line.(2).The distribution of Pt/BSO-MS and Pt/BSO-MS-HA in the tumor and various organs was detected by fluorescence imaging.(3).To investigate the antitumor effect of Pt/BSO-MS-HA by measuring the body weight and tumor size of tumor-bearing mice.Results:1.The material properties of Pt/BSO-MS-HA were investigated.It was found that the morphology of Pt/BSO-MS-HA nanoparticles was similar to that of MS nanoparticles.HA modification had no significant effect on the size of MS,with the encapsulation efficiency of 39%and the platinum loading rate of 18.1%.The presence of GSH significantly accelerated the release of Pt.2.The in vitro experiments of Pt/BSO-MS-HA showed that 1)Pt/BSO-MS-HA had a stronger killing effect on cancer cells;2)Pt/BSO-MS-HA was more easily taken up by CAL-27 cells due to the targeting effect of HA;3)BSO is an ideal agent for reducing GSH in CAL-27 cells.3.The in vivo experiments of Pt/BSO-MS-HA showed that Pt/BSO-MS-HA had less toxicity and excellent in vivo anti-tumor effect.Conclusions:In this study,we constructed and synthesized a drug-loaded nanoparticle(named as Pt/BSO-MS-HA)that co-delivered anti-cancer drugs DSCP and BSO with MS as the carrier and HA as the surface modification,in order to improve intracellular drug delivery and enhance tumor inhibition.In vivo and in vitro experiments have shown that Pt/BSO-MS-HA can significantly inhibit squamous cell carcinoma of head and neck progression with low systemic cytotoxicity,and is a new and potential cancer treatment method,which may have many important biomedical applications in the future.