Construction Of Activatable NIR-Ⅱ Fluorescence And Photoacoustic Probes And Research In Precise Diagnosis And Treatment Of Tumors

As a global health problem,malignant tumors seriously threaten human life and health.Although scientists have developed a variety of rapid and effective diagnosis and treatment methods for tumors,the accuracy of tumor imaging and diagnosis,the specificity of treatment,and the evaluation of treatment effe cts are still problems that need to be solved urgently.For the accuracy of tumor imaging and diagnosis,optical imaging,due to its advantages in temporal and spatial resolution,provides a tool for the precise diagnosis of tumors.Among them,photoacoust ic imaging probes,as a basic tool for biomolecular detection and imaging,have high tissue penetration depth and imaging resolution,and have been widely used in tumor diagnosis.However,photoacoustic imaging still has defects such as low imaging signal-to-noise ratio and easy to be affected by probe content and heterogeneous distribution factors,which reduces the accuracy of its diagnosis and imaging.Near-infrared two region（NIR-Ⅱ）fluorescence imaging technology,as one of the fastest developing opt ical imaging technologies in recent years,has the advantages of deep tissue penetration,weak autofluorescence,low light scattering,high resolution,and high signal-to-noise ratio.However,the current NIR-Ⅱ imaging materials are difficult to directly construct activated probes for tumor diagnosis and treatment research due to their shortcomings such as chemical inertness and poor response performance.For effective treatment methods for tumors,photothermal therapy（PTT）,due to its advantages of less trauma and simple operation,has become another new method for tumor treatment after surgery,radiotherapy,chemotherapy and other treatments.But it has the problems of damage to normal surrounding tissue caused by excessive heat and low specificity.Therefore,how to improve the imaging accuracy of optical probes and the specificity of photothermal therapy and other key issues faced in the precise diagnosis and treatment of tumors would be studied in this paper.In this paper,a series of near-infrared（NIR）organic small molecule dyes were designed and synthesized,and a series of novel optical nanoprobes were successfully constructed based on these dyes,which were used for precise imaging and specific treatment of tumors.The details are as follows:（1）In chapter 2,we synthesized a series of NIR molecular dyes with donor-acceptor-donor（D-A-D）framework using BBTD molecule and its derivatives as skeleton,and preliminarily studied their photothermal,photoacoustic and NIL-Ⅱ imaging properties.The results show that the absorption spectrum of the constructed small molecule dye is located in the near infrared region,and the emission spectrum covers the NIR-Ⅱ.At the same time,the constructed small molecule dye has good optical imaging and photothermal properties,which provides a basis for the construction of new optical probe.（2）In Chapter 3,we constructed a nitric oxide NIR-Ⅱ fluorescence imaging nanoprobe F127@A2-Si R-NO based on fluorescence resonance energy transfer mechanism,using the NIR-I probe SIR-NO with high molar extinction coefficient as the donor,and A2 with the NIR-Ⅱ fluorescence emission as the receptor,and applied it to NIR-Ⅱ fluorescence imaging of NO in tumors.The construction of activated near-infrared NIR-Ⅱ fluorescent probe is expected to achieve high sensitivity detection and high contrast imaging of targets in vivo.（3）The activated optical probe realizes the detection of the target,but because its single signal output may be susceptible to external factors such as prob e content,imaging depth,and heterogeneous distribution,it may cause false imaging signal.Therefore,in Chapter 4,we developed a ROS-activated ratiometric optical probe for precision imaging of target molecules.In response to ROS,the probe generates ratiometric NIR-Ⅱ fluorescence(FI_EX915/FI_EX808)signal changes to improve the accuracy of ROS imaging and detction in tumors.（4）For further improve the imaging specificity of a single factor activated ratiometric optical probe.Therefore,in Chapter 5,we constructed a dual-factor（NO and p H）activated ratiometric imaging probe DATN for precise imaging of tumors.The probe can effectively reduce the interference of external factors by two non-interfering detection signals output to improve the accuracy of molecular detection and imaging.Importantly,the dual-factor activation strategy can improve its specificity for tumor imaging in vivo.（5）In view of most current tumor treatment methods（such as chemotherapy,radiotherapy and phototherapy）cause non-specific damage to normal tissues and side effects.In Chapter 6,we continue to apply dual-factor activated platform to improve the specifity of tumors phototherapy.The photothermal properties of the nanoprobe DATN can be activated in tumors during phototherapy,especially in inflammation-related tumors,thus showing good tumor therapeutic effects.This provides new ideas for the construction of precision medicine.