Magnetic resonance molecular imaging of metastatic breast cancer by targeting extradomain-B fibronectin in the tumor microenvironment.

Abstract

Non-invasive early accurate detection of malignant breast cancer is paramount to the clinical management of the life-threatening disease. Here, we aim to test a small peptide targeted MRI contrast agent, ZD2-Gd(HP-DO3A), specific to an oncoprotein, extradomain-B fibronectin (EDB-FN), in the tumor microenvironment for MR molecular imaging of breast cancer. EDB-FN expression in 4T1 and MDA-MB-231 cancers was analyzed with quantitative real-time PCR and western blot. Primary and metastatic triple negative breast cancer mouse models were developed using 4T1 and MDA-MB-231 cells. Contrast-enhanced MRI was carried out to evaluate the use of ZD2-Gd(HP-DO3A) in detecting 4T1 and MDA-MB-231 primary and metastatic tumors. EDB-FN was abundantly expressed in the extracellular matrix (ECM) of both the primary and metastatic TNBC tumors. In T1 -weighted MRI, ZD2-Gd(HP-DO3A) generated superior contrast enhancement in primary TNBC tumors than a nonspecific clinical agent Gd(HP-DO3A), during 30 min after contrast injection. ZD2-Gd(HP-DO3A) also produced a significant increase in contrast-to-noise ratio (CNR) of TNBC metastases, enabling sensitive localization and delineation of metastases that occulted in non-contrast-enhanced or Gd(HP-DO3A)-enhanced MRI. These findings potentiate the use of ZD2-Gd(HP-DO3A) for MR molecular imaging of malignant breast cancers to improve the healthcare of breast cancer patients. Magn Reson Med 79:3135-3143, 2018. © 2017 International Society for Magnetic Resonance in Medicine.