Synthesis Of New Bimodal Luminescence-Magnetic Resonance Imaging Probes For Bioimaging Applications

Bimodal luminescence(fluorescence or phosphorescence)-magnetic resonance imaging(MRI)technique has shown great utilities in bioassays because it combines the advantages of both luminescence imaging(Li)and MRI to provide more sufficient information over any modality alone.In recent years,developments and applications of bimodal luminescence-MRI probes(contrast agents)have become one of hot spots in bioimaging researches.Different kinds of luminophores and magnetic resonance contrast agents have been combined for designing molecular or nanosacaled bimodal probes,which allows various bioimaging detections to be achieved.In this dissertation,by conjugating polypyridine-ruthenium(?)complex luminophores having excellent photophysical properties with some magnetic resonance contrast agents,several functional molecular and nanoscaled bimodal luminescence-MRI probes were designed and synthesized,and successfully used for biological imaging researches.A novel heterobimetallic Ru(?)-Gd(?)complex,Ru-Gd,comprising a luminescent Ru(?)complex,[Ru(bpy)2(phen)]2+(bpy:2,2'-bipyridine;phen:1,10-phenanthroline),and a Gd(?)complex,DoTA-Gd3+(DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid),has been designed and synthesized as a magnetoluminescent bimodal imaging probe.The complex Ru-Gd is water-soluble,biocompatible with low cytotoxicity,strongly luminescent with a long luminescence lifetime and a large Stokes shift,and has a comparable longitudinal relaxivity(r1=4.71 mM-1 s-1),which enables the complex to be suitable for luminescence bioimaging and Ti-weighted MRI.Using Ru-Gd as a contrast agent,the T1-weighted MRI of a Kunming mouse was successfully performed.The results demonstrated the potential of Ru-Gd for bimodal bioimaging applications.On the basis of adsorption and luminescence quenching effect of MnO2 nanosheets on[Ru(bpy)3]Cl2,a bimodal luminescence-MRI nanoprobe for glutathione(GSH)was prepared.The nanoprobe,Ru(BPY)3@MnO2,is weakly luninescent with very low longitudinal and transverse relaxivity.In the presence of GSH,the reduction of MnO2 nanosheets by GSH produces a number of Mn2+ ions,a perfect MRI contrast agent,and simultaneously triggers the release of[Ru(bpy)3]Cl2 to make the remarkable luminescence enhancement,which enables GSH to be detected under luminescence and magnetic resonance two modes.The nanoprobe showed good biocompatibility and rapid,selective,and sensitive response toward GSH.Using the long-lived emission feature of Ru(?)complex in the probe,background-free time-resolved luminescence detection of GSH in human sera was realized.In addition,the practicability of the nanoprobe was proved by luminescence imaging of endogenous GSH in living cells,zebrafish,and tumor-bearing mice,as well as the MRI of GSH in tumor-bearing mice.By covalently conjugating a hypochloric acid-responsive Ru(?)complex,[Ru(bpy)2(AN-bpy)](PF6)2[AN-bpy:4-methyl-4'-(4-amino-3-nitro-phenoxy-methylene)-2,2'-bipyridine],with a Gd(?)complex DOTA-Gd3+,a novel heterobimetallic Ru(?)-Gd(?)complex,Ru-AN-Gd,was synthesized to serve as an effective probe for bimodal luminescence-magnetic resonance imaging of HClO in vitro and in vivo.The specific reaction between Ru-AN-Gd and HCIO triggers the cleavage of ether bond in probe molecule,resulting in luminescence turn-on and MR turn-off responses to HCIO.The integration of MR and luminescence detection modes allows the probe to be employed for detecting HClO in a wide concentration range(1-2000?pM),and for imaging HClO at various resolutions ranging from subcellular level to the whole body without a depth limit.Using Ru-AN-Gd as a probe,the luminescence imaging of HCIO in live cells,visualizations of HClO generation in zebrafish inflammation model and mouse arthritis model were realized.Furthermore,by the bimodal luminescence-MR imaging of HCIO in drug-induced acute liver and kidney injury of mice,the potential of Ru-AN-Gd for the diagnosis of HCIO-relative diseases was demonstrated.