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Finding NEMO's Switchable MRI Signal Using Microfluidic Tumor Models

使用微流控肿瘤模型寻找 NEMO 的可切换 MRI 信号

基本信息

批准号：
10652001
负责人：
Margaret Bennewitz
金额：
$ 44.46万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652001
关键词：
3-Dimensional Address Anxiety Award Benign Biodistribution Blood Blood Vessels Brain Breast Cancer Cell Breast Cancer Detection Breast Cancer Early Detection Breast Magnetic Resonance Imaging Cancer Detection Cancerous Cell Culture Techniques Cell Survival Cells Characteristics Clinic Clinical Trials Coculture Techniques Complex Analysis Confocal Microscopy Contrast Media Data Devices Early Diagnosis Encapsulated Endosomes Endothelial Cells Engineering Ensure Environment Evaluation Exhibits Extracellular Matrix Extracellular Space Formulation Gadolinium Goals In Vitro Label MRI Scans Macrophage Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammography Medical Care Costs Medical Imaging Medical Waste Metals Methods Microfluidic Microchips Microfluidics Modeling Mucin 1 protein Mus Normal tissue morphology Outcome Patient-Focused Outcomes Peptides Performance Perfusion Physiological Public Health Research Resolution Safety Science Screening procedure Signal Transduction Skin Specificity Testing Time Toxic effect Training Universities West Virginia Work bone breast cancer diagnosis cancer cell cell growth chelation cytotoxicity density follow-up high throughput screening imaging agent imaging detection improved in vivo innovation malignant breast neoplasm manganese oxide microdevice nano nanomaterials neoplastic cell novel optical imaging orthotopic breast cancer overexpression particle portability preclinical development preclinical study recruit supplemental screening tumor undergraduate student uptake young woman

项目摘要

PROJECT SUMMARY Misdiagnosis is prevalent in younger women with dense breast tissue receiving breast cancer screening, resulting in missed cancers, needless follow-up testing, anxiety, and medical costs. Compared to mammography, magnetic resonance imaging (MRI) detects more breast cancers but still suffers from high false positive rates due to the conventional contrast agents used, 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. By remaining active, Gd-chelates produce high background signal in normal tissues and highlight both benign and malignant tumors. To address our long-term goal, we have developed Nano-, Encapsulated Manganese Oxide (NEMO) particles that will provide superior replacements for Gd-chelates. Our preliminary data shows that NEMO particle specificity is achieved by adding peptide targeting to underglycosylated mucin-1, which is overexpressed exclusively on breast cancer cells. NEMO particles provide a unique pH-switchable signal that is only activated upon internalization in acidic tumor cell endosomes (pH 5). No MRI signal is produced at pH of the blood (pH 7.4) or tumor extracellular space (pH 6.5). Our in vivo studies demonstrate that NEMO particles are safely tolerated in mice and exhibit a stronger signal than Gd-chelates. Currently, no high throughput method exists for testing new MRI contrast agents that predicts in vivo performance. The goals of the current project are to develop an innovative portable apparatus to enable evaluation of the sensitivity, specificity, and safety profile of NEMO particles vs. Gd-chelates using MRI and optical imaging of 3D microfluidic tumor models. Our central hypothesis is that NEMO particles will elicit low toxicity, specifically label breast cancer cells, and yield higher MRI contrast compared to Gd-chelates in 3D microfluidic tumor models and in mice with breast cancer. Our hypothesis will be tested with two aims: 1) Evaluate NEMO particle vs. Gd-chelate MRI contrast in 3D microfluidic tumor models and mice. 2) Evaluate toxicity and distribution of NEMO particles in 3D microfluidic tumor models and mice. This project is innovative because NEMO particles uniquely respond to endosomal pH to generate contrast only inside breast cancer cells to provide a simple binary readout (benign “OFF”, malignancy “ON”). Previously developed pH-sensitive MRI contrast agents respond to the acidic extracellular space, which is similar in benign and malignant tumors. We will also create a novel apparatus to enable MRI of 3D microfluidic tumor models for the first time. The proposed research is significant because we will demonstrate that NEMO particles have superior specificity, signal strength, and safety compared to Gd-chelates. This R15 award will offer cutting- edge training to undergraduates in nanomaterials and medical imaging research at West Virginia University. Over 3 years, 6 undergraduates pursuing engineering or biomedical sciences degrees will be recruited, trained, and assessed. This work will lead to further preclinical development and clinical trials of NEMO particles.

项目总结