Development of uMUC-1 Targeted NEMO Particles with pH-Activatable MRI Signals for Enhanced Detection of Malignant Breast Cancer Cells

Magnetic resonance imaging (MRI) detects more breast cancers than mammography due to its superior soft tissue contrast; however, it still misdiagnoses 40% of benign tumors as malignant due to clinically used nonspecific contrast agents (e.g., gadolinium chelates). To overcome this limitation, we developed receptor-targeted, pH-sensitive Nano-Encapsulated Manganese Oxide (NEMO) particles as an alternative <i>T</i>₁-weighted MRI contrast agent. A breast cancer targeting peptide, EPPT, against underglycosylated mucin-1, promotes preferential endocytosis of NEMO particles by malignant cells and specific activation of the MRI signal inside low pH endosomes/lysosomes. In just 30 min, EPPT-NEMO particles produced rapid and robust <i>T</i>₁-weighted MRI contrast inside T47D breast cancer cells that reached ∼276% signal enhancement, which was significantly brighter than MCF10A benign control cells (∼57% enhancement). Mn cellular content further confirmed peptide targeting specificity, while confocal microscopy showed the colocalization of EPPT-NEMO particles with endosomes and lysosomes. EPPT-NEMO particles show promise as alternative <i>T</i>₁-weighted MRI contrast agents, producing significantly brighter signals in breast cancer cells compared to benign cells within clinically relevant timeframes. These advancements in targeted MRI contrast agents could lead to improved accuracy in breast cancer diagnosis and ultimately to better patient outcomes.