Synthesis Of Ferroptosis-bascd Multi-targeted Nanomedicines And Investigate The Role In The Comprehensive Treatment Of Glioblastoma

Glioblastoma is the most malignant tumor in the central nervous system,and the prognosis of patients is dismal because of the low curative rate and easy recurrence after surgery,radiotherapy and other comprehensive treatment strategies.Although new approaches such as immunotherapy and chimeric antigen receptor T-Cell immunotherapy have been established,few of them have been proven to be effective in clinical trials of glioblastoma.The treatment of glioblastoma involves challenges such as blood-brain barrier,immune evasion,Warburg effect,and cell heterogeneity,etc.It is essential to explore and construct medications that target the biological characteristics of glioblastoma to overcome these obstacles,and related therapies are expected to break the therapeutic bottleneck of glioblastoma and achieve the goal of prolonging the survival of patients.Drug combination therapies have shown many benefits in the treatment of glioblastoma,as multi-drug combinations can maximize the anti-tumor effects of these drugs while significantly reducing systemic toxicities and overcoming the development of drug resistance in tumor cells caused by a single medication.The construction of nanomedicines is an ideal way to achieve multi-drug combinations.With the contribution of nanocarriers,different therapeutic drugs can be synergistically integrated into the carriers to enhance the efficacy and safety of the carried drugs.Compared with traditional chemotherapeutic drugs,nanomedicine synthesis,as the most innovative field of drug development,has shown the following advantages in the antiglioblastoma field.To address the problem of inferior drug delivery in glioblastoma,the advantages of nanomedicines are as follows:(1)nano-formulations can facilitate the passage of drugs through the blood-brain barrier;(2)nanomedicines with diameters less than 200 nm can rely on enhanced permeability and retention effects to achieve local enrichment of tumors;(3)modification of tumor-targeting ligands can enable nanomedicines to bind to highly expressed receptors on the cell surface and improve the capacity of positive uptake.In overcoming glioblastoma heterogeneity and chemoresistance,nanomedicines can achieve therapeutic goals by(1)improving the efficacy of chemotherapeutic drugs by promoting the endocytosis of drugs;(2)enhancing tumor radiosensitization and increasing the effect of radiotherapy;(3)activating the immune mechanisms of anti-tumor immune cells,such as T cells and NK cells;(4)inhibiting tumor angiogenesis;(5)clarifying tumor boundaries to facilitate surgical resection;(6)evade tumor surveillance/defense system to enter inside the tumor;and(7)restores tumor cell death pathways.The purpose of this study is to explore the synthesis of multi-targeted nanodrugs and their mechanism of effect in the treatment of glioblastoma,and to explore their advantages over nonnanodrug therapeutic systems.Two nanodrugs,designed and constructed in this study,were designed and constructed for drug combination and treatment from different perspectives,and both therapeutic modalities were aimed at solving the above-mentioned problems and achieving the above-mentioned therapeutic goals.In the first chapter,a multi-targeted synergistic nanomedicine FA/Pt-si-GPX4@IONPs based on iron oxide nanoparticles was designed and constructed,which can effectively deliver iron,cisplatin and glutathione peroxidase 4,thus efficiently and synergistically inducing ferroptosis and apoptosis.In addition to local tumor injection,the nanodrug significantly improved the positive uptake efficiency of tumor cells through surface-modified folic acid ligands.The mounted therapeutic agents overcame the problems of tumor heterogeneity and chemoresistance by inducing two types of cell death,enhanceing the combined therapeutic effect of each combination drug,and reduced the toxic side effects caused by intravenous injection.In the second chapter,to address the drawbacks identified in the first chapter,such as the difficulty of local injection and the discrepancy with clinical application,the second chapter focuses on the construction of nanomedicines that can penetrate the blood-brain barrier by controlling the drug size to make it easier to cross the damaged blood-brain barrier,in addition to the targeting group cRGD,which can also increase the local uptake of tumor,both of which can increase the drug concentration in the tumor.In response to the problems of tumor heterogeneity and chemoresistance,the synthesized nanodrug RPDGs carry additional drugs,namely doxorubicin,tetravalent platinum drugs and gallic acid,which significantly improve the combined therapeutic effect.Notably,RPDGs had significantly higher effect in terms of efficiency in inducing ferroptosis in tumor cells with better therapeutic efficacy compared to FA/Pt-si-GPX4@IONPs.In conclusion,this study constructed two multi-targeted nanodrugs that induce ferroptosis,overcoming the drawbacks of blood-brain barrier,tumor heterogeneity and chemoresistance,significantly improving the therapeutic efficacy of the drugs,overcoming the challenges of poor effect and systemic toxicity of traditional drugs,and providing new ideas for the development and construction of therapeutic drugs for glioblastoma.