Novel Benzo-bis(1,2,5-thiadiazole)Fluorophores For In Vivo NIR-? Tumor Imaging And Image-guided Surgery

Near-infrared fluoreseence imaging has advantages such as noninvasiveness,high temporal resolution,high spatial resolution,non-radiation and low cost,which has draw increasing interest in biomedical imaging area.Compared with traditional near-infrared fluorescence imaging(NIR-I)of which wavelength is mainly at 650-900nm area,near-infrared window ?(NIR-?)fluorescence imaging has much longer imaging wavelength(1000-1700nm),lower tissue scatter,less absorption,negligible autofluorescence,lower signal-to-background ratio(SBR)and deeper imaging resolution.Recently,NIR-? imaging has gained numerous significant applications.Although most commonly used NIR-? fluorescence dyes are quantum dots,rare-earth element nanoparticles etc.,unfavorable drawbacks of these probes including slow metabolism and high toxicity which strongly hindered the clinical translation of these probes.Therefore,it is urgent and significant to develop novel NIR-? probes with better metabolism rate,lower toxicity and higher quantum yield.According to molecular simulative computing,we designed five potential core skeletons,based on which eight novel small molecular probes Ql,Q4,HI,HCQB,HCQF,HCQI,HCQ2 and HCQ3 were synthsized accordingly.Among them,compounds Ql,Q4,and H1 were encapsulated into a PEGylated surfactant DSPE-PEGs000,which led to water-soluble NIR-? nanoparticles CQS1000,Q4NPs and HINPs respectively.Upon injection of CQS1000 to rear paw of nude mice,lymphatic vessels connecting the injection site with the sentinel lymph node,as well as the afferent and efferent lymphatic vessels could be unambiguous distinguished.Compared with NIR-? imaging probe ICG,the lymphatic vessel visualized in the NIR-? window(CQS1000)showed two folds of feature sharpness enhancement(583.3±11.30 ?m vs.1160.2 ±27.41 ?m)and three folds of SBR increase(4.41 ± 0.27 ?m vs.1.44 ± 0.15 ?m).Besides,precise NIR-?image-guided xenogeneic tumor and sentinel lymph node(SLN)removal surgerys were successfully applied with HINPs and CQS1000,respectively.In addition,in order to increase tumor specificity,SCH1100 was prepared through conjugation of Q4 with peptide RM26,SDH was prepared through conjugation of HI with peptide RGDfk.Blocking experiments demonstrated that SCH1100 and SDH were specifically targeted PC3 and U87MG tumor,respectively.Futher more,HCQB,HCQF,HCQ1,HCQ2 and HCQ3 were solvent-dependent probes,which have different fluorescence intensity and fluorescence wavelength in different orgnic slovents,and HCQF is the first reported reversible pH-sensitive NIR-? probe.Importantly,quaternary ammonium salt HCQFS and HCQF-PEGS could switch the fluorescence signal from blank(HCQF and HCQF-PEG5000 in water)to ultralight in water,which can be further used as NIR-? "tum-off"probes.In conclusion,in this thesis we described the design and syntheses of eight NIR-? probes,which were further used for tumor imaging,blood vessels imaging,lymph node imaging and image-guided xenogeneic tumor removal surgerys.These NIR-? fluorescence probes are taking a prominent role for the clinical translation.