NIR-â…¡ Small Organic Molecule Fluorophores For Surgical Navigation And Photothermal Therapy Of Tumor

In recent years,near-infrared Ⅱ（NIR-â…¡,1000-1700 nm）fluorescence imaging has developed rapidly due to its higher imaging depth and excellent resolution compared with visible light（400-700 nm）and near-infrared I（NIR-I,700-900 nm）fluorescence imaging.In the past five years,a great number of near-infrared â…¡ fluorescent probes of organic small molecules have been prepared for near-infrared â…¡ biomedical imaging.As a result,they have excellent biocompatibility,rapid excretion and other advantages.Therefore,organic small-molecule NIR-â…¡ probes are one of the most promising candidates for future clinical applications.Herein,a PET/NIR-â…¡ dual-modality probe composed of a NIR-â…¡ organic small molecule with excellent tumor targeting ability was prepared by thiol-based click chemistry.Subsequently,the PET and NIR-â…¡ dual-modality tumor imaging and NIR-â…¡ image-guided tumor surgical navigation using this outstanding dual-mode probe was further explored.Moreover,through the electrostatic non-covalent interaction between sulfonate and cetuximab protein,a theranostic agent composed of a NIR-â…¡ organic small molecule was prepared,which had remarkable tumor-targeted imaging and photothermal therapy effect for colon cancer in in vivo and in vitro.The main contents of the thesis are as follows.Firstly,a PET/NIR-â…¡ dual-modality probe with integrin αvβ3 targeting function based on thiol-yne click chemistry was constructed for tumor delineation and image-guided surgery of gliomas.In this study,we have developed a novel,simple and effective strategy using base-catalyze thiol-yne click to prepare a NIR-â…¡/PET dual-modal probe(⁶⁸Ga-CHS2)with high chemo-selectivity.This probe contains targeting peptide RGD,which target integrin αvβ3 receptors.In addition,⁶⁸Ga-CHS2 has a highly selective targeting ability for U87MG tumor cells that overexpress αvβ3 integrin receptors.The evaluations of PET/NIR-â…¡ imaging and image-guided surgery were performed in the nude mice bearing U87MG xenografts.Excellent PET/NIR-â…¡ dual-modality imaging qualities,high tumor uptake,high tumor and normal tissue contrast ratio,precise tumor delineation,and accurate NIR-â…¡ image-guided tumor surgery were successfully achieved in the tumor mice model.Secondly,the sulfonate modified NIR-â…¡ organic dye-Cetuximab complex is used in the study of NIR-â…¡ image-guided tumor photothermal therapy.In this study,a simple and feasible organic synthesis method in three steps was used to prepare the hydrophobic NIR-â…¡ dye H2a.After removing of trimethylsilyl alcohol protecting group of H2a,taurine was introduced into the NIR-â…¡ fluorophores by amide condensation reaction to obtain a water-soluble compound H2a-4T.Then,H2a-4T and fetal bovine serum（FBS）or the Ig G1 monoclonal antibody cetuximab that targeted the epidermal growth factor receptor（EGFR）were simply mixed to prepare H2a-4T@FBS or H2a-4T@Cetuximab complex.H2a-4T@FBS complex can be used for mouse lymph nodes NIR-â…¡ imaging,image-guided lymph node dissection.Furthermore,H2a-4T@Cetuximab complex has a very high photothermal conversion efficiency,can be used for in vivo NIR-â…¡ targeting imaging of HCT 116 colon cancer with EGFR over-expression and NIR-â…¡ image-guided tumor photothermal therapy.The tumor of the photothermal treatment group using H2a-4T@Cetuximab complex combined with laser irradiation is completely ablation.