| Glioma is the most common primary brain tumor.The possible cause of glioma is that the cancerous glial cells in the brain and spinal cord grow along nerve fibers and diffuse into surrounding brain regions.Because of its extremely aggressive and intracranial heterogeneity,the median survival duration of patients is only 14.6 months.Maximum resection combined with chemotherapy and radiotherapy is the primary clinical treatment for current adult primary gliomas.However,it is difficult to identify the anatomical boundaries by the clinic imaging technology due to its infiltrative growth.Moreover,the blood-brain barrier(BBB)prevents most of the drugs from being delivered to the brain,resulting in the unsatisfactory treatment effect.Rare earth luminescent nanomaterials have potential applications in the biomedical field because of their unique advantages,such as tunable excitation/emission,narrow half-peak width,high photochemical stability and easy surface modification.In particular,the near-infrared(NIR)light can penetrate the skull,making rare earth luminescent nanomaterials expected to provide new strategies for the diagnosis and treatment of glioma.Based on this,the following research was carried out in this thesis:1.Yttrium vanadate-based nano-theranostics agent with excellent near infrared two-region(NIR-Ⅱ)emission was designed and constructed(YHM).The successful modification of lactoferrin(LF)endowed it with good ability to cross the BBB.Meanwhile,the excellent near-infrared fluorescence properties in the second window(NIR-Ⅱ)of YVO4:Nd3+core allowed YHM to be used as a probe for NIR-Ⅱfluorescence imaging.In the tumor microenvironment(TME),the MnO2 shell not only can generated oxygen to relieve tumor hypoxia and improve the efficacy of sonodynamic therapy(SDT),but also can be degraded to Mn2+ for T1-weighted magnetic resonance imaging(MRI)of orthotopic glioma.The YHM can serve as a contrast agent for dual-modality NIR-Ⅱ fluorescence imaging/MRI for imaging diagnosis of orthotopic glioma,which also effectively inhibited the growth of glioma through the safe and non-invasive SDT.2.A new nano-theranostics agent YOF:Nd3+@MnO2-ICG-GOx-LF(labeled as YMIGL)was prepared.The modification of LF endowed YMIGL with good ability to cross the BBB and target glioma cells.The strong NIR-Ⅱ luminescence of YOF:Nd3+ core made YMIGL as the potential NIR-Ⅱ fluorescent imaging probe for realizing the imaging diagnosis of orthotopic glioma.Glucose oxidase(GOx)and MnO2 shell significantly increased the oxygen production and glucose consumption capacity of the YMIGL through a cascade reaction,thus enhancing the therapeutic effect of photodynamic therapy(PDT)of indocyanine green(ICG)and realizing starvation therapy(ST).YMIGL achieved efficient PDT and ST synergistic treatment through a cascade reaction,which successfully inhibited the growth of orthotopic glioma.3.Near-infrared light-excited iron-based metal framework nanodrugs(UMDL)were constructed for the treatment of orthotopic glioma.NH2-MIL-53(Fe),a photosensitizer,was coated on the surface of rare earth ions doped up-conversion nanocrystals(NaGdF4:Yb,Tm@NaYF4:Yb,Nd@NaYF4,UCNPs),and its the porous structure can be used as a carrier for loading chemotherapy drug doxorubicin hydrochloride(Dox).Finally,the modification of LF on the outermost layer endowed UMDL with the ability to traverse BBB and target glioma cells.UCNPs were able to convert 808 nm near-infrared(NIR)light to ultraviolet(UV)light for exciting NH2-MIL-53(Fe),achieving NIR light-mediated PDT.In addition,the Fe3+on the surface of NH2-MIL-53(Fe)were reduced to Fe2+ by glutathione(GSH)in TME,and then Fe2+ further reacted with the overexpressed hydrogen peroxide(H2O2)to generate hydroxyl radicals(·OH)for chemodynamic therapy(CDT).Dox can be released in TME with weak acidity and GSH overexpression,which greatly reduced the side effects on normal tissues.The synergistic effect of PDT/CDT/chemotherapy achieved the effective suppression effect for orthotopic glioma. |
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