Construction,Performance Control And Application Of High Performance Rare-earth Fluoride Multifunctional Optical Theranostic Nanoprobe

As is known to all,it is vitally important to elevate the early tumor diagnosis efficiency and timely intervention to improve the survival rate of cancer patients.Therefore,the development of advanced,efficient,and highly sensitive diagnosis technology is the key factor to solve the problem.Among the various imaging modals,optical imaging,which is recognized as a non-invasive method for in vivo real-time detection of disease progression,has played an important role in the early diagnosis of tumor.In recent years,multi-functional optical theranostic nanoprobes and nanomaterials assisted immunotherapy have greatly improved the diagnosis and treatment efficiency of diseases.In particular,lanthanide based multi-functional nanomaterials,which integrate a variety of diagnosis and treatment methods into one to achieve high sensitivity detection and efficient treatment of early tumors,has been widely used in basic scientific research.However,the early diagnosis and treatment efficiency is still limited by the shallow tissue penetration depth of the excitation and emission light and the poor cure effect of single treatment mode.Therefore,it is urgently needed to construct a high performance multifunctional,optical theranostic nanoprobe for deep tissue tumor detection and treatment.Based on these facts,this thesis takes rare earth fluoride optical imaging nanoprobe as the research object,and aims to build the high-performance rare-earth fluoride optical theranostic nanoprobe for highly sensitive optical guided deep tissue tumor diagnosis and effective treatment,laying the foundation of designing new type of high sensitivity multifunctional optical theranostic nanoprobe.The main contents of this thesis are listed as follows:(1)A luminescence regulation method based on Ce³⁺doping was developed to construct the hexagonal phase Na Ln F₄ nanoprobe.By utilizing the cross relaxation(CR)between Er³⁺and Ce³⁺,the down-shifting near-infrared II(NIR-?,1000-1700 nm;1400-1600 nm,defined as NIR-?b)emission of Er³⁺was significantly enhanced.We have successfully demonstrated high spatial resolution optical imaging of the tumor vascular by using the probe,revealing the distribution trend of the tumor vascular,and further realized the optical imaging guided tiny(?3mm)metastasis tumor detection.Therefore,this study further expands the application of rare earth based nanoprobes in NIR-? optical imaging,and provides a new strategy for high sensitivity detection of early deep tissue tumors.(2)A small hexagonal phase Na Lu F₄:Yb/Gd/Er@Na YF₄core-shell nanoprobe with enhanced NIR-?b emission,high photostability and controllble size was developed by using a core-shell method to avoid surface quenching effect and Ce³⁺doping strategy.We then successfully demonstrated the high sensitivity deep tissue NIR-? optical imaging of acute kidney injury.The research provides a new method for the noninvasive optical imaging guided high sensitivity diagnosis of deep tissue diseases.(3)Through interface and Ce/Er energy transfer,808 nm light excited rare earth-based Na Ln F₄ core-shell optical nanoprobe with significantly enhanced NIR-?b fluorescence intensity(?11 times)by using Nd³⁺as a photosensitizer was constructed.Compared with the traditional 980 nm light excited rare-earth nanoprobe,the excitation wavelength of the probe was shifted to 808 nm by using the Nd³⁺-sensitized strategy,which successfully eliminated the 980 nm laser induced tissue overheating effect.Through surface functionalization,we have successfully realized the high spatial resolution visualization of the tumor edge/vascular and demonstrated the NIR-?b optical-guided surgery of tumor.Therefore,the constructed NIR-?b optical probe has shown great potential in the diagnosis of early tumors and optical imaging guided tumor resection.(4)In order to break through the tissue penetration depth limitation of near-infrared light,we have further designed the X-ray light excitated Na Ln F₄:Gd/Tb@Na Ln F₄ small hexagonal phase nanoscintillators with the precise control of the phase structure and optical properties,and the luminescent mechanism of the nanoscintillator was also revealed.A soft X-ray-responsive CO release gas sensor was further constructed via loading photo-responsive CO releasing moiety(Photo CORM)and deep tissue(>5 cm)CO release was achieved via soft X-ray irradiation.Furthermore,deep tissue CO gas mediated cancer therapy was demonstrated by using the probe.It was found that the CO gas can further adjust the tumor immunosuppressive microenvironment and thus promote the systemic adaptive immune response,and the mechanism of CO gas activated immunotherapy was also revealed for the first time.This work provides a new strategy of designing soft X-ray light activated nanoprobe for synergistic deep tissue gas/immunotherapy of cancer.