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.

项目概要在接受乳腺癌筛查的乳腺组织致密的年轻女性中，误诊很常见，与乳房X光检查相比，会导致漏诊癌症、不必要的后续检查、焦虑和医疗费用，磁共振成像 (MRI) 可检测出更多乳腺癌，但假阳性率仍然很高由于使用传统造影剂，例如钆 (Gd) 螯合物，我们的长期目标是开发。用于乳腺癌早期检测的新型安全造影剂，可减少假阳性和假阴性 Gd 螯合物的性能较差是由于其缺乏靶向性和恒定的 MRI 信号。通过保持活性，Gd 螯合物在正常组织中产生高背景信号，并突出显示良性组织为了实现我们的长期目标，我们开发了纳米封装锰。我们的初步数据表明，氧化物 (NEMO) 颗粒将成为 Gd 螯合物的优质替代品。 NEMO 颗粒特异性是通过向糖基化不足的 mucin-1 添加肽靶向来实现的，即 NEMO 颗粒专门在乳腺癌细胞上过度表达，可提供独特的 pH 可切换信号。仅在酸性肿瘤细胞核内体（pH 5）中内化时激活，在 pH 值时不产生 MRI 信号。血液 (pH 7.4) 或肿瘤细胞外空间 (pH 6.5) 我们的体内研究表明 NEMO 颗粒。在小鼠中是安全耐受的，并且表现出比 Gd 螯合物更强的信号，目前尚无高通量方法。存在用于测试预测体内性能的新 MRI 造影剂当前项目的目标是。开发一种创新的便携式设备，以评估灵敏度、特异性和安全性使用 MRI 和 3D 微流体肿瘤模型的光学成像来比较 NEMO 颗粒与 Gd 螯合物的比较。假设 NEMO 颗粒会产生低毒性，特异性标记乳腺癌细胞，并产生更高的产量 3D 微流体肿瘤模型和乳腺癌小鼠中 MRI 与 Gd 螯合物的对比。假设将通过两个目标进行检验：1) 评估 3D 微流体中 NEMO 粒子与 Gd 螯合 MRI 的对比 2) 评估 NEMO 颗粒在 3D 微流控肿瘤模型中的毒性和分布这个项目是创新的，因为 NEMO 颗粒对内体 pH 值有独特的反应以产生。仅在乳腺癌细胞内部进行对比，以提供简单的二进制读数（良性“关”，恶性肿瘤“开”）。先前开发的pH敏感的MRI造影剂针对酸性细胞外间隙，这与我们还将创建一种新的设备来实现 3D 微流控肿瘤的 MRI。首次提出的模型非常重要，因为我们将证明 NEMO 粒子与 Gd 螯合物相比，该 R15 具有卓越的特异性、信号强度和安全性。为西弗吉尼亚大学纳米材料和医学成像研究本科生提供边缘培训。 3年内，将招募、培训6名攻读工程或生物医学科学学位的本科生，这项工作将导致 NEMO 颗粒的进一步临床前开发和临床试验。