ABSTRACT
Gadolinium(III) ion (Gd(3+)) complexes are widely used as contrast agents in magnetic resonance imaging (MRI), and many attempts have been made to couple them to sensor moieties in order to visualize biological phenomena of interest inside the body. However, the low sensitivity of MRI has made it difficult to develop practical MRI contrast agents for in vivo imaging. We hypothesized that practical MRI contrast agents could be designed by targeting a specific biological environment, rather than a specific protein such as a receptor. To test this idea, we designed and synthesized a Gd(3+)-based MRI contrast agent, 2BDP3Gd, for visualizing atherosclerotic plaques by linking the Gd(3+)-complex to the lipophilic fluorophore BODIPY to stain lipid-rich environments. We found that 2BDP3Gd was selectively accumulated into lipid droplets of adipocytes at the cellular level. Atherosclerotic plaques in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits were clearly visualized in T1-weighted MR images after intravenous injection of 2BDP3Gd in vivo.
Subject(s)
Boron Compounds/chemistry , Contrast Media/chemistry , Coordination Complexes/chemistry , Fluorescent Dyes/chemistry , Gadolinium/chemistry , Plaque, Atherosclerotic/diagnosis , Adipocytes/metabolism , Adipocytes/pathology , Animals , Aorta/metabolism , Aorta/pathology , Aorta/ultrastructure , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Contrast Media/administration & dosage , Coordination Complexes/administration & dosage , Drug Design , Injections, Intravenous , Lipid Droplets/metabolism , Magnetic Resonance Imaging , Mice , Mice, Knockout , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , RabbitsABSTRACT
Gadolinium ion (Gd(3+)) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T(1)-weighted MR images. Recently, several methods to achieve cell-permeation of Gd(3+) complexes have been reported, but more general and efficient methodology is needed. In this report, we describe a novel method to achieve cell permeation of Gd(3+) complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit. We synthesized Gd(3+) complexes conjugated with boron dipyrromethene (BDP-Gd) and Cy7 dye (Cy7-Gd), and showed that these conjugates can be introduced efficiently into cells. To examine the relationship between cell permeability and dye structure, we further synthesized a series of Cy7-Gd derivatives. On the basis of MR imaging, flow cytometry, and ICP-MS analysis of cells loaded with Cy7-Gd derivatives, highly hydrophobic and nonanionic dyes were effective for enhancing cell permeation of Gd(3+) complexes. Furthermore, the behavior of these Cy7-Gd derivatives was examined in mice. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to improve the cell permeability of Gd(3+) complexes, and should be applicable for further development of Gd(3+)-based MRI contrast agents.
Subject(s)
Carbocyanines/chemistry , Carbocyanines/metabolism , Contrast Media/chemistry , Contrast Media/metabolism , Gadolinium/chemistry , Magnetic Resonance Imaging/methods , Animals , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , HeLa Cells , Humans , Hydrophobic and Hydrophilic Interactions , Male , Mice , Mice, Inbred BALB C , Molecular Structure , NIH 3T3 CellsABSTRACT
Based on the findings that the azo functional group has excellent properties as the hypoxia-sensor moiety, we developed hypoxia-sensitive near-infrared fluorescent probes in which a large fluorescence increase is triggered by the cleavage of an azo bond. The probes were used for fluorescence imaging of hypoxic cells and real-time monitoring of ischemia in the liver and kidney of live mice.
