Contruction And Biogical Application Of Near Infrared Er³⁺/Tm³⁺ Activated Core-Shell Nanoprobes

The near infrared（NIR）rare earth doped nanocrystals are a class of novel inorganic nanoprobes with unique optical property,which are widely used in vivo imaging,phototherapy and biosensing.However,these nanocrystals suffered from low quantum yield,lack of compatibility with therapeutic model and hardly in vivo quantitative analysis using luminescence intensiy,limiting their biological research on integration of diagnosis and treatment.To overcome these problems,three efficient rare earth doped nanoprobes were constructed by regulating core/shell structure,according to the Na Ln F₄ nanocrystals with a hexagonal crystallographic phase and low phonon energy state.These probes realized high-constast bioimaging,image-guided photothermal therapy and quantitative detection of the oxidative stress markers.The main research contents are summarized as follows:High contrast optical in vivo imaging was performed with NaErF₄:Yb@Na Lu F₄nanoprobes.Under 808 nm NIR laser irradiation,the effect of doping Er³⁺ions concentration in Na YF₄:x%Er@Na Lu F₄on 1525 nm NIR-Ⅱluminescence was investigated via varying the doping concentration of Er³⁺ions.The optimal doping concentration of Er³⁺ions in the system was determined to be 100%,and the high1525 nm luminescence intensity was obtained.On the basic of 100%Er³⁺ions doping,Yb³⁺ions were introduced and optimized its doping concentration for enhancing1525 nm luminescence of Er³⁺ions.As a result,the core-shell nanocrystals of NaErF₄:20%Yb@Na Lu F₄ can generate brighter luminescence intensity（quantum yield was 11%）,and successfully penetrated 11 mm chicken tissue under 808 nm excitation.Coating polyacrylic acid（PAA）,NaErF₄:20%Yb@Na Lu F₄ core-shell nanocrystals was transfered to water phase and injected intravenously for the high contrast optical imaging of blood vasculature in the mouse brain.Rare earth-prussian blue theranostic agents（NaErF₄@Na YF₄@NaNdF₄@Prussian blue）were constructed for NIR luminescence imaging guided photothermal therapy（PTT）.For 980 nm light excitation,the 1525 nm luminescence of Er³⁺ions from interior NaErF₄@Na YF₄@NaNdF₄ core/shell/shell nanocrystals was investigated for NIR-Ⅱimaging.Under 808 nm light excitation,the photothermal enhancement of prussian blue to rare earth nanocrystals was studied,and demonstrated that the cross-relaxation between Nd³⁺ions,and new cross-relaxation pathways between Nd³⁺ions and prussian blue were the main reson for PTT.These theranostic agents had excellent NIR optical absorption and photothermal transformation performance（photothermal conversion was 50.5%）,resulting in⁸0%death of He La cells.Finally,NIR-Ⅱluminescence imaging guided PTT was realized by injection of the rare earth-prussian blue theranostic agents in the mouse tumor model,and effectively surpressed the tumor（the tumor size shrunk 12-fold compared to the tumors without treatment）.In addation,luminescence imaging also monitored the PTT process and evaluated the therapy.In vivo quantitative analysis and dynamic monitoring the markers of oxidative stress were realized using the rare earth-prussian blue luminescent probes（Na YF₄@Na Yb F₄@Na Yb F₄:Tm@Na YF₄@Prussian blue）.The overlap between luminescence spectra of Na YF₄@Na Yb F₄@Na Yb F₄:Tm@Na YF₄ nanocrystals and absorption spectra of prussian blue was investigated for illustrating the luminescence resonance energy transfer effect,which resulted the suppression of 800 nm luminescence lifetime of Tm³⁺ions.In the presence of different concentrations of oxidative species,the lifetime recovery of the rare earth-prussian blue luminescent probes was analyzed,and used for constructing a standard curve of oxidative stress markers.To improve the selectivity,the hydrocyanine 5（Hcy5）,an activatble dye,was introdeced as a competitor to protect rare earth-prussian blue luminescent probes from O₂·^–.Combined with NIR luminescence lifetime is independent of tissue penetration depth,the prepared luminescent probes were applied for ONOO^–and Cl O^–lifetime imaging at different time points in the hepatotoxicity and inflammation model of mice,realizing quantitative measurement and monitor of biomarkers.