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

Significance The normal prostate gland contains the most Zn(II) of all mammalian tissues, and there are marked differences in Zn(II) content between the healthy, malignant, and benign hyperplastic prostate. Given that multiparametric MRI does not always reliably distinguish between these tissue conditions, the release of Zn(II) ions from the prostate in response to an external stimulus may prove valuable as a specific biomarker of prostate cancer progression. In this work, we show that glucose stimulates the release of Zn(II) from intracellular stores in healthy prostate tissue and that Zn(II) secretion is reduced in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. 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 T1-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.