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

项目总结-肿瘤靶向ph敏感氧化锰纳米颗粒增强乳房

PROJECT SUMMARY - Tumor-targeted pH-sensitive manganese oxide nanoparticle for enhanced breast cancer detection using MRI Breast cancer screening is plagued with high rates of misdiagnosis for younger women with dense breast tissue. These women are subjected to needless follow-up testing including painful biopsies, increased anxiety, and higher medical costs. Compared to mammography, magnetic resonance imaging (MRI) detects more breast cancers yet suffers from high false positive rates due to the clinically used contrast agents, e.g., gadolinium (Gd)- chelates. Our long-term goal is to develop novel, safe contrast agents for early detection of breast cancer that reduce the false positives and false negatives of breast MRI. The poor performance of Gd-chelates results from their lack of targeting and constant MRI signal. Gd-chelates highlight both benign and malignant tumors and achieve lower contrast due to the high background signal produced in normal tissues. To address our long-term goal, we developed Nano-, Encapsulated Manganese Oxide (NEMO) particles as superior replacements for Gd- chelates. Our preliminary data shows we have successfully decorated NEMO particles with a peptide that targets underglycosylated mucin-1 (uMUC-1), which is overexpressed exclusively on breast cancer cells to ensure selectivity. Upon uptake by cancer cells into acidic endosomes (pH 5), NEMO particles generate a unique pH- switchable signal. Minimal signal is produced at pH of blood (pH 7.4) and tumor extracellular space (pH 6.5). NEMO particles create a stronger signal vs. Gd-chelates and are safely tolerated in vivo. It is necessary to test the efficacy of contrast agents via MRI; however, MRI cannot detect small scale nanoparticle-multicellular interactions in real-time. Thus, the goals of the current project are to apply a novel, integrated approach of MRI and intravital fluorescence imaging via a technique that incorporates a window surgically implanted over the mammary tumor in mice for long-term visualization to correlate MRI signal with fluorescent nanoparticle-cell dynamics. We hypothesize that NEMO particles will selectively label breast cancer cells, yield higher MRI contrast, and elicit low toxicity in breast cancer mouse models versus conventional Gd-chelates. We propose the following aims: (1) Determine sensitivity and selectivity of NEMO particle MRI signal in breast cancer models, (2) Assess NEMO particle-cell interactions in the tumor microenvironment with optical imaging, and (3) Evaluate safety and pharmacokinetics of NEMO particles in vivo. There are three main innovations for this project: First, uMUC-1 targeted NEMO particles will generate contrast only in breast cancer cells to produce a simple binary readout (benign “OFF”, malignancy “ON”). Second, we will develop a novel MRI compatible intravital window to evaluate real-time dynamic nanoparticle-cell interactions in breast tumors. Third, we will test unexplored intravascular contrast agent safety mechanisms in human blood and mouse models. The proposed research is significant, as improved MRI contrast agents will expedite, simplify, and enhance breast cancer MRI diagnosis. Our multimodal platform will be applicable to other cancers and will enable new directions in evaluating MRI theranostic agents. This work will lead to future clinical trials of NEMO particles for enhanced cancer detection.