Advancing NEMO’s specific MRI detection of residual breast cancer using novel imaging platforms

About This Grant

PROJECT SUMMARY Magnetic resonance imaging (MRI) is the most accurate method for sensitive detection of residual breast cancer following neoadjuvant chemotherapy. However, standard MRI contrast agents (gadolinium (Gd)-chelates) have low specificity, which leads to tumor overestimation and greater mastectomies. Compared to breast-conserving surgery, mastectomy has negative psychological impacts, reduced breast aesthetics, and decreased long-term patient survival. We currently lack improved contrast agents for accurate imaging of therapeutic response. My long-term goal is to create novel contrast agents for safe and precise breast cancer detection. Towards this goal, my laboratory has developed Nano-Encapsulated Manganese Oxide (NEMO) particles as a new pH-sensitive tumor specific MRI contrast agent. NEMO particles are localized to breast cancer cells through peptide targeting to underglycosylated mucin-1 (uMUC-1), overexpressed in cancer. Once internalized by cancer cells, NEMO particles dissolve in acidic endosomes/lysosomes, producing a robust pH-activated MRI signal in ~30 minutes. Our in vivo preliminary data in mouse models demonstrates that NEMO particles are safely tolerated after multiple injections and are rapidly eliminated from systemic organs in 24 hours. In vivo, NEMO particles detect breast cancer with higher specificity and equivalent contrast to Gd-chelates. The objective of this project is to develop improved breast MRI of therapeutic response using NEMO particles and to advance their translational potential using cutting-edge imaging tools developed by my lab. Our team is pioneering microfluidic MRI of organon- a-chip models for high throughput in vitro contrast testing under dynamic flow. We have also developed a proof-of-concept breast tumor imaging platform with a dual MRI and fluorescence intravital imaging window to correlate MRI signal with NEMO’s distribution at the cellular level. We will test the central hypothesis that NEMO particles will enhance specificity compared to Gd-chelates in detecting residual breast cancer post neoadjuvant chemotherapy using the following Specific Aims: (1) Optimize uMUC-1 targeted NEMO particle’s sensitivity and specificity by microfluidic MRI, (2) Establish NEMO particle sensitivity, specificity, and toxicity in preclinical breast cancer models and (3) Evaluate NEMO particle sensitivity and specificity post neoadjuvant chemotherapy. Breast cancer mouse models will supplement microfluidic studies to test in vivo contrast agent vascular delivery, biodistribution, systemic toxicity, and contrast intratumoral accumulation pre/post chemotherapy. This project has three innovations: First, we created uMUC-1 targeted NEMO particles that uniquely activate in endosomal pH to produce MRI contrast in breast cancer cells. Second, microfluidic MRI on in-house chips will test contrast agent dynamics in tumor spheroids under flow for the first time. Third, our new MRI/fluorescence imaging window will probe NEMO’s tumor uptake on cell and tissue levels to assess treatment response. Our research is significant, as NEMO particles will more accurately image residual breast cancer to enable more breast conserving surgeries. This work will lead to future clinical trials of NEMO particles for enhanced cancer detection.