The Applications Of Nano-composites Based On Lanthanide-doped Upconversion In The Treatment Of Alzheimer’s Disease

Alzheimer’s disease（AD）is one of the most prevalent neurodegenerative diseases and generally affects patient’s central nervous system.Alzheimer’s disease often occurs in older people over the age of 65.As China’s aging population intensifies,the incidence rate of Alzheimer’s disease is increasing year by year.Alzheimer’s disease seriously affects the physical and mental health of the elderly people.At the same time,it brings a heavy burden to the economy and society.However,until now,the pathogenesis of Alzheimer’s disease is still unclear,which makes it harder to find an effective cure for this disease.Therefore,the realization of effective diagnosis and treatments of Alzheimer’s disease is a significant challenge for the scientific community.In recent years,with the development of nanotechnology,and the continuous intersection of nanotechnology and biomedicine,more and more researchers turn their attention to the application of nanomaterials in the diagnosis and treatments of Alzheimer’s disease.The multifunctional nanocomposites can be used for the diagnosis and treatment of AD mainly focused on Aβfibrils and Tau protein.These nanocomposites can also be used to detect and scavenge the overexpressed reactive oxygen species.In this dissertation,the lanthanide-doped upconversion nanoparticles（UCNPs）were successfully synthesized by the high-temperature thermal decomposition method.Then through proper surface modification and drug loading,the obtained multifunctional nanocomposites can inhibit the aggregation of AD pathological proteins.Meanwhile,the features of multifunctional nanocomposites,including luminescence property,drug release ability,biocompatibility,and potential biological application,were further explored in this dissertation.The main contents are summarized as follows:（1）The core-shell multifunctional nanocomposite UCNPs-LMB based on lanthanide-doped upconversion nanoparticles was designed and synthesized successfully by surface modification.The UCNPs-LMB multifunctional nanocomposite can be excited by the 980 nm near-infrared light.Due to the overexpressed reactive oxygen species in AD patients’brain,this multifunctional nanocomposite can respond to HOCl rapidly,leading to the controlled release of fluorophore methylene blue（MB）.MB acts as an effective inhibitor for inhibiting Tau protein aggregation and it was proved by Th T fluorescence test and circular dichroism test.Er³⁺is doped into UCNPs,which can be used as an activator for converting the980 nm near-infrared light to the visible light at 655 nm.The 655 nm light activated photosensitizer MB for producing the singlet oxygen（¹O₂）,which can degrade Aβaggregates and reduce its biotoxicity to the surrounding tissues.Both in vitro and cell experiments showed that UCNPs-LMB multifunctional nanocomposite could respond to HOCl rapidly and release MB for effectively inhibiting Tau protein aggregation and photo-depolymerizing Aβaggregates under near-infrared light irradiation.The cytotoxicity assay showed that UCNPs-LMB multifunctional nanocomposite had high biocompatibility.More importantly,UCNPs-LMB can reduce the cytotoxicity of AD pathological protein to PC12 cells and improve the cell viability.（2）UCNPs@m Si O₂-MB@Au NPs multifunctional nanocomposite was successfully constructed for inhibitting Aβand Tau protein aggregation.We chose mesoporous silica（m Si O₂）coated UCNPs as a nano-delivery system for delivering drug MB.Besides,theβ-D-glucose modified gold nanoparticles（Au NPs）can react with 4-carboxyphenylboric acid modified UCNPs@m Si O₂ forming a borate bond to form the UCNPs@m Si O₂-MB@Au NPs nanoparticles.Au NPs was chosen to seal the mesoporous silica pores to avoid the premature drug MB release from UCNPs@m Si O₂.The borate bond can specifically respond to reactive oxygen species in the lesions to achieve the controlled released effects of MB.The outermost layer of this multifunctional nanocomposite is Au NPs and it is used for inhibiting the aggregation of Aβmonomers effectively,which was proved by Th T fluorescence and circular dichroism tests.Due to the overexpressed H₂O₂ in AD patients’brain,Au NPs were cut off from the surface of UCNPs@m Si O₂ by breaking the borate bond.The drug MB released from the mesoporous silica pores for inhibiting Tau protein aggregation.Meanwhile,UCNPs dropped with Er³⁺showed bright upconversion luminescence at 650 nm under the irradiation of 980 nm near-infrared light,which matched well with the absorption spectrum of MB at 650 nm.Therefore,a ratio upconversion fluorescent nanocomposite was successfully constructed for the detection of drug MB releasing effect.Both in vitro and cell experiments showed that UCNPs@m Si O₂-MB@Au NPs multifunctional nanocomposite could respond to H₂O₂rapidly and release MB from the mesoporous silica pores.The cell experimental results showed that UCNPs@m Si O₂-MB@Au NPs multifunctional nanocomposite exhibited low toxicity.It can effectively inhibit Aβand Tau protein aggregation.Moreover,this nanocomposite can also reduce the cytotoxicity of AD pathological protein to PC12 cells and improve the cell viability.（3）UCNPs@m Si O₂-curcumin@Cu_xO multifunctional nanocomposite was successfully constructed for inhibitting Aβaggregation and eliminating excessive expressed reactive oxygen species.We chose nano-drug delivery system UCNPs@m Si O₂ and drug curcumin loaded into the mesoporous silica pores.Cu_xO NPs attached onto UCNPs@m Si O₂ by positive and negative charges attraction.Curcumin can gradually release from mesoporous silica pores to monitor the aggregation extent of Aβand inhibit Aβaggregation,which was proved by Th T fluorescence test and circular dichroism test.Cu_xO NPs can effectively eliminate a variety of reactive oxygen species and reduce the damage caused by oxidative stress.In vitro results showed that UCNPs@m Si O₂-curcumin@Cu_xO nanocomposite could effectively increase the accumulation of drug curcumin in the brain,and enhance the inhibition effect of Aβprotein aggregation.