Tumor-targeted pH-sensitive manganese oxide nanoparticle for enhanced breast cancer detection using MRI

Bennewitz, Margaret

Abstract

Approximately 2.1 million women globally will be diagnosed with breast cancer each year and over 626,000 women will die because of it. Triple negative breast cancer (TNBC) is the most aggressive subtype, with the greatest potential to metastasize and recur despite treatment. Our long-term goal is to develop an innovative contrast agent for enhanced early detection of TNBC recurrence that will greatly reduce the false negatives and false positives associated with current breast imaging techniques. Magnetic resonance imaging (MRI) detects more breast cancers than mammography; however, false positive diagnoses remain high with MRI due to the standard contrast agent used (e.g. gadolinium chelate). Gadolinium chelates are non-targeted MRI contrast agents that always generate signal, which leads to the inability to accurately distinguish benign from malignant tumors. Our approach is drastically different. Herein, we will develop novel tumor-targeted pH-activatable manganese oxide (MnO) nanoparticles (NPs) for early and specific breast cancer MRI detection. MnO NPs present a targeting peptide that binds to underglycosylated mucin-1 (uMUC-1) overexpressed on breast cancer cells. MnO NPs will be endocytosed specifically by cancer cells and dissolved in low pH endosomes to release Mn2+ ions to initiate MRI signal. Unlike conventional MRI, our targeted MnO NPs will specifically detect malignant tumors but not benign tumors, as uMUC-1 is only present on breast cancer cells. By reducing false positives, our approach will avoid unnecessary biopsies, surgery, further imaging, anxiety, and save up to $3 billion in medical bills annually. In addition, MnO NPs can promote detection of smaller tumors, as Mn2+ has higher relaxivity than gadolinium chelates and NPs can deliver more Mn2+ to the cancer site. Due to earlier diagnosis and prompt treatment enabled with our detection strategy, patient survival will be significantly increased. We hypothesize that uMUC-1 targeted pH-activatable MnO NPs will specifically label malignant breast tumors expressing uMUC-1 in vivo and produce sufficient MRI contrast to visualize smaller tumors than conventional gadolinium chelates. We will test this hypothesis with the following aims: 1) Design targeted pH-activatable MnO NPs to preferentially accumulate within TNBC tumors expressing uMUC-1 in vivo. 2) Determine degree of toxicity and biodistribution of targeted MnO NPs. 3) Establish potential of targeted pHactivatable MnO NPs for detecting smaller TNBC tumors compared to Multi Hance.