Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate

Abstract

Many secretory tissues release Zn(II) ions along with other molecules in response to external stimuli. Here we demonstrate that secretion of Zn(II) ions from normal, healthy prostate tissue is stimulated by glucose in fasted mice and that release of Zn(II) can be monitored by MRI. An ∼50% increase in water proton signal enhancement is observed in T 1 -weighted images of the healthy mouse prostate after infusion of a Gd-based Zn(II) sensor and an i.p. bolus of glucose. Release of Zn(II) from intracellular stores was validated in human epithelial prostate cells in vitro and in surgically exposed prostate tissue in vivo using a Zn(II)-sensitive fluorescent probe known to bind to the extracellular surface of cells. Given the known differences in intracellular Zn(II) stores in healthy versus malignant prostate tissues, the Zn(II) sensor was then evaluated in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model in vivo. The agent proved successful in detecting small malignant lesions as early as 11 wk of age, making this noninvasive MR imaging method potentially useful for identifying prostate cancer in situations where it may be difficult to detect using current multiparametric MRI protocols.prostate | cancer | glucose | zinc | MRI

Generalizing, Extending, and Maximizing Nitrogen-15 Hyperpolarization Induced by Parahydrogen in Reversible Exchange

“…Thus, low-field NMR and MRI with SABRE may enable high sensitivity NMR and MRI for a large audience at moderate cost with many applications. 65,66 …”

High‐Field Detection of Biomarkers with Fast Field‐Cycling MRI: The Example of Zinc Sensing

“…The maximum signal enhancement is about 166 %u pon the addition of 1equivalent of Zn 2 + ,i nc ontrast to no signal enhancement detectedw ith standard MRI at the nominal field strength of 2.89 T. Thisi sq uite remarkable because, even at the most optimal field (0.5 T), the relaxivityc hange upon Zn 2 + -binding is only 26 %f or this probe (see NMRD profile). [18] These studies werep erformed at 9.4 T, where relaxometric data predicta bout 50 %r elaxivity response to Zn 2 + .Inarecent study,Z n 2 + was imaged with another contrast agentp roviding ar elaxivity response of only 7.5 %a tt he imaging field of 9.4 T. [19] With the FFC-MRIt echnique, remarkably highers ignal variations are achieved. [16] Similarr elaxivity response (165 %) was obtained for the most-studied t R -activated contrasta gent at 0.5 T; [13c] however,a th igherf ield the response decreases dramatically.T his last agent was used in vivo to detect Zn 2 + in the pancreas [17] or in prostatec ancer.…”

Probes for monitoring regulated exocytosis

“…Since light penetration or scattering may become a limiting factor for optical imaging in live animals, novel concepts and strategies would be required. Some emerging approaches have yielded promising results for in vivo studies, including intravital microscopy or microendoscopy [18, 60, 61], in vivo ACEE-Tagging followed by postmortal analysis [20], and magnetic resonance imaging [45, 62]. Future exploration of these and other imaging technologies will offer exciting opportunities for investigating physiological regulation of stimulus-secretion coupling in vivo.…”

“…ZIMIR binds Zn 2+ with a K d of 0.45 µM and displayed a 70-fold enhancement in fluorescence intensity upon Zn 2+ binding. In addition to cultured cells, ZIMIR also labeled cells in tissues such as pancreatic islets and prostate glands [43–45]. , Confocal ZIMIR imaging in isolated islets revealed that beta cells were fairly heterogenous in their secretory responses to glucose stimulation, with small clusters of islet beta cells exhibiting potent insulin/Zn 2+ secretion activity surrounded by non-secretory cells [43].…”