Design,Synthesis,and Angiography Of NIR-Ⅱ Cyanine Dyes

Fluorescence imaging technology is a promising method for accurate diagnosis and treatment of diseases with high detection sensitivity and ability to achieve molecular and cellular imaging.However,conventional fluorescence imaging is mainly located in the visible to NIR-I region(650-950 nm).Short wavelengths(< 1000 nm),especially the visible spectrum,result in poor photon penetration depth,which remains a major limitation for clinical applications of biomedical fluorescence imaging in vivo.Compared to visible and NIR-I imaging,near-infrared II imaging(NIR-Ⅱ,1000-2000 nm)not only enables real-time monitoring of deep tissue,but also allows intraoperative navigation to remove lesions,with promising clinical applications such as significantly reduced light scattering,reduced tissue autofluorescence,and increased water absorption.In recent years,with the rapid development of NIR-Ⅱ fluorescence imaging,the demand for NIR-Ⅱ fluorophore is huge and urgent,but the high performance NIR-Ⅱ fluorophore is still limited.NIR-Ⅱ cyanine probes show high quantum yield(QYs),good biocompatibility and satisfactory pharmacokinetics.However,the conjugated framework of long-wavelength polygamichuachuan dyes are vulnerable to water attack,resulting in fluorescence quenching.As a result,efforts are ongoing to develop bright,stable,and biocompatible NIR-Ⅱ fluorescence with longer wavelengths(> 1000 nm).Based on the advantages of NIR-Ⅱ cyanine probes in the aspects of NIR-Ⅱ imaging,this paper constructs eight kinds of NIR-Ⅱ organic small molecule probes by molecular engineering modification of FD-1080,and uses encapsulation scheme in bovine serum albumin(BSA)to improve their brightness and stability.We then succeeded in identifying two binding sites for Et-1080,St-1080,CO-1080 and FD-1080,where CO-1080 @ BSA provides high quality imaging studies of angiography and lymphoma.This paper is mainly divided into the following four chapters:The first chapter is a literature review.Firstly,the origin and development of NIR-Ⅱ fluorescence imaging are briefly reviewed,and then the challenges and problems faced by NIR II fluorescence imaging are discussed.To date,a number of strategies have been established for the development of NIR-Ⅱ fluorophores and fluorescent probes for high-resolution and sensitive imaging of biological NIR-Ⅱ in deep tissues.In this paper,the design and regulation strategies of the photophysical properties of Nil-II cyanine dyes and the application of NIR-Ⅱ bioimaging are introduced.Finally,we also summarize the challenges and clinical limitations of NIR-Ⅱ polymethylene dyes.In Chapter 2,eight cyanine dyes in near-infrared-II were prepared.The dyes form D-π-A structure with benzoindole as the end-donor group,which increasing the electron density of the donor is beneficial to the emission peak red shift.Their absorption and emission peaks are located at 1046/1078 nm,and the chlorine-containing dyes have better optical properties than the bromine containing dyes of the same series.Therefore,we selected Et-1080,St-1080,CO-1080 and FD-1080 to further systematically evaluate the optical properties.The results show that CO-1080 has higher relative quantum yield and molar extinction coefficient,and can be used for NIR-Ⅱ fluorescence imaging.In the third chapter,the nonradiative attenuation induced by vibration relaxation must be overcome,collisional quenching and π-π stacking of synthetic cyanine dyes in a solution of PBS.In this paper,a strategy of inserting 1080 series dye into the hydrophobic pocket of bovine serum albumin(BSA)was proposed to stabilize the dye molecules and improve its physiological brightness.Furthermore,using high-resolution mass spectrometry data and molecular dynamics simulations,the 1080 cyanine dyes were successfully distinguished from albumin in two binding regions,as well as non-covalent bond interaction strengths.We also compared the ability of four free dyes and dye-protein complexes to image the vascular and lymphatic systems in mice,demonstrating that CO-1080@BSA can be used for superior contrast and real-time NIR-Ⅱ imaging of the vascular and lymphatic systems.This work provides the feasibility of encapsulating NIR-Ⅱ cyanine dyes with bovine serum albumin and broadens the prospect of clinical application of NIRII fluorophore.In chapter 4,the synthesis of cyanine dyes and dye-albumin and the reaction mechanism of NIR-Ⅱ dye-albumin complex are reviewed,which provides new ideas for improving their biocompatibility and luminescence properties.After that,we follow the strategy of theoretical exploration and practical application research in this paper,and look forward to the next step.