Fabricatioin And Application Of Charge-reversible Dual-emissive Persistent Luminescence Theranostic Nanoprobe

Cancer continues to threaten human health and it’s urgent to develop effective cancer diagnosis and treatment strategies.Persistent luminescence nanoparticles（PLNP）can store excitation energy and slowly release luminescence after excitation stops.The feature of in situ excitation-free gives PLNP outstanding advantages of no tissue autofluorescence interference for in vivo imaging.However,current PLNP is limited to single-wavelength emission and susceptible to the luminescence variation with time after stopping excitation,which impedes further development of PLNP in bioimaging.Dual-emissive probe can perform self-calibration reading and ratio imaging by detecting the fluorescence intensities at two different wavelengths,thereby effectively avoiding the interference of external factors.Dual-emissive PLNP,therefore,is expected to achieve constant ratio imaging with a long detection window,promoting the biomedical applications of PLNP.The aim of this thesis is to develop the controllable synthesis of dual-emissive monodispersed PLNP（Zn Ga₂O₄:Cr）for persistent luminescence ratio bioimaging as well as the rational design of dual-emissive PLNP-based charge-reversible intelligent theranostic nanoprobe for imaging-guided chemo-photothermal synergic therapy.The main results are as follows:Dual-emissive PLNP Zn Ga₂O₄:Cr_0.0001 was prepared by controlling the content of chromium,hydrothermal and calcination conditions.The as-prepared PLNP gave two characteristic emission peaks at 508 nm and 714 nm and was still detected up to 60 min after excitation stopped.In addition,the persistent luminescence could be re-activated with both red LED lamp and 254 nm UV irradiation.Although the persistent luminescence of each emission decreased significantly with time,the ratio of the persistent luminescence intensities for the two emission peaks(I₅₀₈/I₇₁₄)was generally stable even after reactivation,effectively avoiding the great variation of luminescence with time in single-emissive PLNP.Moreover,the prepared PLNP gave a constant I₅₀₈/I₇₁₄ ratio signal in in vivo imaging even after five repeated reactivations by a red LED lamp,and offered great potential for long-term precision in vivo luminescence ratio imaging.The excellent persistent luminescence ratio imaging performance of the synthesized PLNP was employed to develop an intelligent theranostic nanoprobe.A polydopamine（PDA）layer was first grown on the surface of the PLNP to prepare PLNP@PDA.Functionalized polyethylene glycol（NHS-PEG-DMMA）was further introduced onto the surface of PLNP@PDA through the condensation reaction.The resulting PLNP@PDA@DMMA was used to load an anti-cancer durg of doxorubicin hydrochloride（DOX·HCl）byπ-πstacking and electrostatic adsorption to construct the final chemo-photothermal synergic theranostic nanoprobe PLNP@PDA@DMMA/DOX.The synthesized theranostic probe was well monodispersed and stable with the hydrodynamic size of 131.4±35.1 nm and a polydispersion index of 0.195.The synthesized theranostic probe had good photothermal properties.Low p H and 808 nm laser irradiation can synergistically promote controlled release of DOX from the probe.The zeta potential of the probe was-11.60±5.88 m V under normal physiological conditions while 9.02±4.35 m V under acidic conditions.The charge reversal was successfully realized,which provided the possibility for the follow-up tumor targeting and image-guided chemo-photothermal synergetic therapy.The intelligent theranostic probe was applied for imaging-guided tumor therapy.It had no obvious cell dark toxicity,but showed good killing effect of cancer cells under 808 nm laser irradiation as well as good targeted imaging performance of tumor cells.In vivo experiments further confirmed that the fabricated probe had the ability of tumor targeting ratio imaging and good synergistic effect of chemo-photothermal therapy without obvious toxic and side effects.This work provided a new strategy and method for the fabrication and application of the integrated platform of intelligent diagnosis and treatment.