Synthesis And Application Of Eu(Ⅲ)-Gd(Ⅲ) Complex-based Bimodal Probes For Time-gated Luminescence/Magnetic Resonance Bioimaging

In recent years,rare earth luminescent complexes have been well developed as fluorescent probes.The combination of them and time-gated luminescence（TGL）techniques can effectively eliminate interference of background fluorescence and dramatically improve the sensitivity of fluorescent detection.However,fluorescence imaging has the disadvantages of weak tissue penetration and low spatial resolution.Therefore,the combination of TGL and magnetic resonance imaging（MRI）,which is characterized by superb spatial resolution,unlimited tissue penetration,can realize both advantages of the two technologies in one probe and provide more complete anatomical and molecular information of biological target objects.Furthermore,it can effectively reduce the risk of misdiagnosis by generating two signatures from the same diseased tissue.In this dissertation,two bimodal TGL/MR imaging probes based on Eu（Ⅲ）-Gd（Ⅲ）complexes have been designed and synthesized,and their applications in dual-mode detection of cancer cells and physiologically active components were investigated.Firstly,MRI contrast agent（DO3A-Gd）and tumor-targeting biomacromolecule,transferrin（Tf）were covalently coupled toβ-diketone ligand CDHH,respectively.Then Eu³⁺ions were added to the mixture of two functionalizedβ-diketone ligands,which triggered a self-assembly to form a heteronuclear bimetallic Eu（Ⅲ）-Gd（Ⅲ）complex,Tf-Eu-Gd for tumor-targeting bimodal TGL/MR imaging.The as-prepared probe,Tf-Eu-Gd,exhibits intense long-lived luminescence（?=0.20,?=0.34 ms）,remarkably high MR relaxivities(r₁=9.18 m M^-1s^-1,r₂=12.03 m M^-1s^-1),as well as good water solubility,stability and biocompatibility.The utilities of Tf-Eu-Gd have been demonstrated by TGL imaging of cultured cancerous cells and bimodal TGL/MR imaging the tumors in tumor-bearing mice.Based on the finding that pentafluorobenzenesulfonate can be specifically cleaved by hydrogen peroxide（H₂O₂）,a bimodal TGL/¹⁹F MR imaging probes,Mito-PFTTA-Ln³⁺(Ln³⁺=Eu³⁺/Gd³⁺),for H₂O₂ in mitochondria were designed and synthesized.The probe Mito-PFTTA-Eu³⁺show"turn-off"TGL response to H₂O₂,its TGL intensity gradually decreases with the increase of H₂O₂ concentration.The dose-dependent TGL decrease shows good linearity between the TGL intensity and the H₂O₂ concentration（limit of detection is14.9 n M）.Furthermore,the intensities of ¹⁹F NMR absorption peaks of Mito-PFTTA-Gd³⁺are dramatically increased in the present of H₂O₂,which shows"turn-on"¹⁹F MR response to H₂O₂.The as-prepared probe exhibits high sensitivity and selectivity,fast reaction rate and mitochondria-targeting function.The feasibility of Mito-PFTTA-Eu³⁺has been estimated by TGL imaging of mitochondrial H₂O₂ in living cells.