Design And Synthesis Of Small-molecule Dyes And Biological Imaging In The Second Near-infrared Window

The high efficiency,high resolution and non-invasive characteristics of optical fluorescence imaging technology is of great significance in biomedical diagnosis and treatment.At the same time,the cost of optical imaging is much lower than that of magnetic resonance imaging and nuclide imaging.Therefore,optical imaging technology and its application have attracted many researchers’ attention.However,the depth of tissue penetration and imaging signal-to-noise ratio are badly affected by light scattering,light absorption by tissues and self-fluorescence of organisms.It is found that increasing the wavelength of the emitted light to the second near-infrared(NIR-II,1000-1700 nm)window is one of the most effective methods to improve this optical imaging defect.Although there are abundant kinds and quantities of probes with NIR-II fluorescence,the number of small molecule probes with the most clinical research value is relatively small.And the maximum emission wavelengths are located in a small range of 1000-1100 nm.In order to enrich the types of small molecule probes in NIR-II window and further improve the emission wavelength,a kind of modifiable small molecule dyes with emission wavelength more than 1100 nm was designed and synthesized by changing the types of heteroatoms and the structure of polymethylene chain based on the resonance molecular structure of FDA-approved indocyanine green(ICG).And it can be applied to many kinds of biological imaging,such as tumor detection,angiography,lymph node searching and so on.Firstly,this paper designs the small moleculer dyes refering the framework structure of cyanine dyes which is well-known in the near infrared region(NIR-I,700-900 nm)such as ICG(fluorescence emission wavelength 822 nm).Two substituted heteroatoms are replaced by nitrogen with oxygen or sulfur,and the length of the intermediate chain of the two heteroatoms is changed and halogen atoms are introduced.A series of heteroatoms substituted polymethane dyes were synthesized by five-step reaction.The range of their maximum emission wavelength is 1000-1170 nm.Not only the emission wavelength of these small molecular dyes has been successfully extended to NIR-II window,but also the maximum absorption of thiopolymethylene dyes has been extended to more than 1000 nm.The series of small molecular dyes have high molar absorptivity and fluorescence quantum yield.Secondly,in order to make up for the vacancies of small molecule dyes in NIR-IIa(1300–1400 nm)and NIR-IIb(1500–1700 nm)sub-window,and further improve the signal-to-noise ratio and penetration depth of optical imaging,this paper exploit the extension emission of small molecule 5H5 to NIR-IIa region to perform 1064 nm excitated NIR-IIa tumors and angiography imaging.Compared with the NIR-II imaging stimulated by 808 nm,the tumor to background ratio is three times higher and detectable vessels was more abundant and clearer in angiography imaging.The extension to NIR-IIa sub-window and the prolonging of excitation wavelength can significantly improve the application of optical imaging in various aspects.Finally,in some cases,single imaging modality can not fully meet all the requirements,which requires a multi-modal probe combined advantadges of multiple imaging modalities to achieve quantitative and qualitative analysis in various situations.In this paper,a novel dual-modal molecular probe 5-5-cetuximab-TCO was constructed by shortening the polymethylchuan chain to improve the stability of small molecules and successfully modifying them with monoclonal antibodies and PET probes.The dual-modal probe of PET/NIR-II was applied in NIR-II optical imaging and pre-targeted PET imaging of MDA-MB-231 breast cancer,and NIR-II optical guided tumor and lymph node resection.The dual-modal imaging can not only give full play to the high temporal and spatial resolution of NIR-II imaging,but also combine the accurate quantification of PET imaging,which is a promising imaging mode.