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Enhanced Ferroptosis In Tumor Cells Through Modulation Of Redox And Iron Homeostasis By Magnetic Organic Silica Nanoplatform

Posted on:2024-06-28Degree:MasterType:Thesis
Country:ChinaCandidate:T SongFull Text:PDF
GTID:2544307079962419Subject:Biology
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Ferroptosis is a form of cell death driven by lipid peroxidation and a promising modality for tumor treatment,showing promising applications in overcoming tumor drug resistance and synergizing with radiotherapy and chemotherapy due to its non-apoptotic nature.However,the special lipid metabolism,redox and iron homeostasis in tumor cells limit the ferroptosis-based therapeutic effect.In this study,a magnetic organic mesoporous silica(D@MOs-P)loaded with dihydroartemisinin was constructed to enhance ferrotosis therapy by disrupting redox homeostasis and iron homeostasis.The magnetic nanoparticles were first synthesized by thermal decomposition,coated with mesoporous organic silica containing disulfide bonds,and finally loaded with the reactive oxygen species(ROS)precursor drug dihydroartemisinin.After endocytosis by tumor cells,disulfide bond-mediated glutathione depletion and glutathione peroxidase 4(GPX4)inactivation will lead to the inactivation of antioxidant system in tumor cells,while DHA will generate ROS catalyzed by iron ions in tumor cells,and the above changes will lead to the disruption of redox balance in tumor cells.On the other hand,the magnetic nanoparticles in this nanoplatform can generate magnetic heat and consequently trigger cellular autophagy and autophagy-dependent degradation of ferritin under the effect of alternating magnetic field to achieve the imbalance of tumor iron homeostasis.Both in vitro and in vivo results suggest that D@MOs-P can trigger ferroptosis in tumor cells by disrupting the above two homeostasis and significantly inhibit tumor growth with minimal side effects.In addition,MNPs can provide excellent T2-weighted MR imaging properties.The successful synthesis of the nanoplatform was demonstrated by transmission electron microscopy and dynamic light scattering,with good dispersion and stability and a particle size of about 90 nm,and the successful loading of DHA was verified by FTIR and others.Moreover,D@MOs-P exhibited glutathione depletion as expected,as well as superparamagnetic and magnetothermal effects in in vitro experiments.The disruption of redox homeostasis and iron homeostasis of 4T1 tumor cells by this nanoplatform was verified at the cellular level,and both live-dead cells staining assays and CCK-8 assays confirmed the significant tumor suppressive effect of D@MOs-P-enhanced ferroptosis therapy with a tumor cell survival rate of only 12.05%.In vivo experiments further confirmed the tumor elimination effect of this nanoplatform with good biosafety,and no significant pathological changes were observed in major organs and blood routine examination.Immunofluorescence analysis of tumor tissue sections also demonstrated the disruption of ferroptosis-related homeostasis.
Keywords/Search Tags:Magnetic Organosilica Nanoparticles, Ferroptosis, Redox Homeostasis, Iron Homeostasis
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