A contrast agent for MRI of calcifications in breast cancer

Abstract

Clinical x-ray mammography cannot delineate between hydroxyapatite and calcium oxalate, the respective forms of calcification in malignant and benign breast tumors. The water-poor nature of solid calcifications makes them difficult to image by conventional MRI. Recently, ultra-short echo time (UTE) MRI has enabled detection of solid calcified structures, but it is not specific to the underlying chemical composition. This thesis presents a hydroxyapatite-targeted gadolinium contrast agent for UTE MRI of calcification in malignant breast cancer. The hydroxyapatite-targeted contrast agent was synthesized by conjugating a bisphosphonate, pamidronate, to a gadolinium chelate. Binding specificity was tested by UTE MRI of the contrast agent reacted with hydroxyapatite, calcium oxalate, and other calcium-based crystals. The sensitivity of the contrast agent for hydroxyapatite was evaluated by UTE MRI: the lowest detectable concentration of hydroxyapatite-adsorbed contrast was 1 pM. Longitudinal relaxation time measurements were used to estimate the apparent relaxivity of the hydroxyapatite contrast agent to be >1000 s-I/mM. The targeted agent relaxivity is enhanced more than a 100-fold compared to conventional untargeted gadolinium contrast agents due to the restricted rotational motion of the contrast agent upon binding to a solid surface. In-vivo MRI of systemic delivery of the contrast agent was demonstrated in an animal model for breast cancer with hydroxyapatite calcifications. Pre- and post-contrast UTE MRI were acquired with systemic contrast agent injections. Dual-echo UTE subtraction images between short and long echoes showed specific uptake of the contrast agent to the calcifications. The mean signal intensity of the calcified regions enhanced by 200% between pre- and post-contrast images, posing the hydroxyapatite-targeted contrast agent as a clinical diagnostic for distinguishing benign and malignant calcification forms in breast cancer.