Activatable MR Imaging Probes Activatable magnetic resonance (MR) imaging probes offer the potential to provide unprecedented biological insights. MR probes responsive to Ca2+ flux, Zn2+ flux, reporter genes, enzymatic activity, pO2, and pH have been reported. Potential applications of such probes include direct imaging of neuronal currents, pancreatic islet viability, gene activation, and key elements of the heterogeneous tumor microenvironment. MR allows the interrogation of intact, opaque organisms in three dimensions at cellular resolution (~10 5m) on high field systems and sub millimeter resolution on clinical scanners. The deep tissue penetration and high resolution make MR make it possible to directly translate findings from cells to mice to humans. The fundamental limitation of activatable MR probes that stifles their translation is the difficulty in distinguishing "active" from "inactive" probe. In MRI primarily water is imaged and the probe is detected indirectly by its effect on the water signal. This effect depends on probe concentration and the probe's relaxivity. Relaxivity is dependent on a number of molecular factors including the hydration state of the probe and its rotational diffusion rate. It is possible to design activatable or "smart" probes where the relaxivity changes in response to an environmental stimulus, e.g. the probe is transformed via enzymatic reaction from a low relaxivity state to a high relaxivity state, or the probe's relaxivity changes upon binding an analyte, e.g. calcium. Although relaxivity can be exquisitely sensitive to a stimulus, the MR signal change depends on both relaxivity and probe concentration: two unknowns. In vitro, where concentration does not change, these probes act as elegant sensors. However in vivo, the probe concentration is unknown and changes with time. Relative to normal tissue, concentrations may be higher in diseased tissue due to increased endothelial permeability, or lower because of poor perfusion. Signal change could be a result of distribution of inactive probe or could be due to probe activation. Currently there is no practical way to distinguish active from inactive probe. We propose activatable probes that are completely MR silent in the "off" state. In this way, any change in MR signal after probe injection must be due to activation of the probe. We propose a new paradigm for activatable MR probes based on the reduction-oxidation (redox) chemistry of manganese. Divalent manganese (Mn2+) is a potent MR relaxation agent but Mn3+ is generally a poor relaxor. We will prepare stable manganese complexes that can reversibly convert from a truly MR-off state (Mn3+) to a MR-on state (Mn2+) in the presence of an environmental stimulus. With development of a tunable redox core, it is possible to design probes sensitive to pH, enzymatic activity, ion flux, or specific haptens. In this application we will focus on developing an MR oxygen sensor for hypoxia imaging, where MR signal is only generated in hypoxic regions. We will validate this hypoxia probe in mouse and rabbit tumor models by comparing to direct pO2 electrode measurements, a positron emission tomography hypoxia probe, and blood oxygen level dependent MR.
|Pierre, Valérie C; Allen, Matthew J; Caravan, Peter (2014) Contrast agents for MRI: 30+ years and where are we going? J Biol Inorg Chem 19:127-31|
|Zhu, Jiang; Gale, Eric M; Atanasova, Iliyana et al. (2014) Hexameric Mn(II) dendrimer as MRI contrast agent. Chemistry 20:14507-13|
|Motola, Daniel L; Caravan, Peter; Chung, Raymond T et al. (2014) Noninvasive Biomarkers of Liver Fibrosis: Clinical Applications and Future Directions. Curr Pathobiol Rep 2:245-256|
|Gale, Eric M; Mukherjee, Shreya; Liu, Cynthia et al. (2014) Structure-redox-relaxivity relationships for redox responsive manganese-based magnetic resonance imaging probes. Inorg Chem 53:10748-61|
|Loving, Galen S; Mukherjee, Shreya; Caravan, Peter (2013) Redox-activated manganese-based MR contrast agent. J Am Chem Soc 135:4620-3|
|Gale, Eric M; Zhu, Jiang; Caravan, Peter (2013) Direct measurement of the Mn(II) hydration state in metal complexes and metalloproteins through 17O NMR line widths. J Am Chem Soc 135:18600-8|