Design,Synthesis And Performance Study Of Near-Infrared Fluorescent Probes For Tumor-Related Biomolecules

With the development of human society,cancer has become the second largest killer of human life and health.The current treatment for solid tumors is mainly based on a comprehensive treatment method of surgery combined with radiotherapy and chemotherapy.The goal of tumor surgery is to completely remove the primary tumor and metastases.The surgical outcome and patient prognosis largely depend on whether the tumor can be completely removed.The current surgical treatment mainly relies on the experience of doctors to distinguish tumor tissue boundaries through palpation and visual inspection,which often results in incomplete tumor resection,which in turn leads to tumor recurrence and metastasis.And this resection method is often accompanied by excessive resection of normal tissues,which increases the functional damage to the patient’s organs or tissues.With the rapid development of molecular imaging,surgical navigation based on imaging guidance has ushered in the dawn of solving the above problems.Among various imaging techniques,near-infrared fluorescence imaging has the characteristics of convenient operation,high sensitivity,and little effect of tissue autofluorescence.The development of near-infrared fluorescent probes with excellent performance is the key to realize intraoperative fluorescence image navigation.Based on the advantages of near-infrared fluorescence imaging technology and the limitations of current probes available for surgical navigation,in this paper,a library of near-infrared fluorescent probes for tumor-related biomolecules was constructed by combining rational design and probe screening strategies.At the same time,aβ-galactosidase probe（NIR-β-Gal（linker））with good sensitivity and selectivity was used to realize tumor cell imaging and fluorescence-guided tumor resection in a tumor mouse model.The details are as follows:1)According to the overexpressed markers in tumors,the hydrogen peroxide-responsive probe NIR-H₂O₂,azoreductase-recognizing probe NIR-AZO,nitroreductase-recognizing probe NIR-NTR,NIR-NE for granulocyte elastase,NIR-CES for esterase,NIR-CES2 for carboxylesterase 2,NIR-β-Gal forβ-galactosidase,NIR-Tyr,a probe that recognizes tyrosinase,and confirmed the structures of these compounds by means of mass spectrometry,nuclear magnetic resonance and other characterization methods.2)The response properties（such as stability,detection limit,etc.）of the above probes to related analytes were explored in detail in solvent,and the response mechanism of these probes was discussed.In addition,in response to the poor response of NIR-CES2 and NIR-β-Gal,we synthesized carboxylesterase 2 probes NIR-CES2-OH andβ-galactoside with better response properties through structural optimization.Enzyme probe NIR-β-Gal（linker）.3)In the above work,we found that NIR-β-Gal（linker）had the best response performance,and further tests showed that the probe NIR-β-Gal（linker）also had good thermal stability and selectivity.Furthermore,through cell imaging experiments,we demonstrated that NIR-β-Gal（linker）has good membrane-penetrating ability and can be used for imaging detection ofβ-galactosidase in cells to achieve overexpressedβ-Gal cancer.differentiation of cells.In vivo experiments also showed that the probe can rapidly and selectively monitor endogenousβ-galactosidase activity.Based on this,we constructed a tumor resection mouse model and successfully applied the probe to fluorescence imaging guidance tumor surgical resection.