Design And Synthesis Of ¹⁹F MRI Contrast Agent And Its Application In Imaging

As one of the most mature in vivo diagnostic tools,magnetic resonance imaging?MRI?does not require the use of ionizing radiation and could provide excellent soft-tissue contrast,three-dimensional structure and functional images,making it widely used in both clinical disease diagnosis and biomedical research.However,the most commonly used ¹H MRI suffers from significant background signals and the potential toxicity risk of contrast reagents.In contrast,¹⁹F MRI has received great attention due to negligible background signals.Moreover,¹⁹F also offers distinct advantages over other nuclei,including 100%natural abundance,high gyromagnetic ratio and broad chemical shift.These features facilitate ¹⁹F MRI with promising potential in tumor detecting,drug delivery monitoring and cell tracking.Lung cancer is the most common malignant tumor with the highest incidence and mortality,occurring at a rate of 23%of all cancer cases.However,there are still no effective treatment methods,so accurate early diagnosis techniques are highly desirable.In this thesis,two kinds of ¹⁹F MRI contrast reagents were constructed and applied for the imaging and detection of non-small cell lung cancer A549 xenograft and nitroreductase?NTR?,respectivly.The contrast reagent BDPF bearing tri-modality detectability in a single molecule helps to simultaneously acquire signal near-infrared fluorescence imaging?NIR FLI?,photoacoustic imaging?PAI?and ¹⁹F MRI.Synergistic combination of three imaging techniques provides solutions able to address multiple issues of sensitivity and tissue penetration.BDPF revealed excellent photophysical properties,high photostability,good PA absorption and a single ¹⁹F signal peak,making it well suited for NIR FL/PA/¹⁹F MR tri-modality imaging.In vitro experiments proved BDPF could be well internalized by human non-small cell lung cancer A549 cells and showed low cytotoxicity and good biocompatibility.BDPF was applied for in vivo NIR FL/PA/¹⁹F MRI tri-modality imaging and detecting of A549 xenograft.NTR can be overexpressed in hypoxic tumors,thus the selective and efficient detection of NTR is of great importance.An amphiphilic contrast reagent A1 was composed of the hydrophobic fluorine-containing part and the hydrophilic ammonium salt part via an ether linkage.The contrast agent self-assembled into nanoparticles in water and exhibited excellent stability,low cytotoxicity and NTR responsiveness.After reaction with NTR,the nitro group was reduced and induced an?-1,6-elimination reaction which led to nanoparticles disassembled and ¹⁹F MRS/MRI signal recovery.This contrast agent A1may potentially be used for non-small cell lung cancer diagnosis and hypoxia microenvironment evaluation.