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.

项目摘要在接受乳腺癌筛查的密集乳腺组织的年轻女性中，误诊很普遍，导致错过的癌症，不必要的随访测试，焦虑和医疗费用。与乳房X线摄影相比磁共振成像（MRI）检测到更多的乳腺癌，但仍然患有高误报率由于使用了常规的对比剂，例如Gadolinium（GD） - chelates。我们的长期目标是发展新颖的，安全的对比剂，用于早期检测乳腺癌，以减少假阳性和假否定性乳房MRI。 GD螯合物的性能不佳是由于它们缺乏靶向和持续的MRI信号而导致的。通过保持活跃，GD氯酸盐在正常组织中产生高背景信号，并突出显示两者良性和恶性肿瘤。为了解决我们的长期目标，我们开发了纳米式锰氧化物（NEMO）颗粒将为GD螯合物提供优越的替代。我们的初步数据表明 Nemo颗粒特异性是通过将胡椒靶向添加到潜在的粘蛋白1来实现的，仅在乳腺癌细胞上过表达。 Nemo颗粒提供了独特的pH开关信号仅在酸性肿瘤细胞内体内内化后激活（pH 5）。在pH的pH下未产生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颗粒在小鼠中安全耐受性耐受性，并暴露于GD螯合物的信号更强。目前，没有高通量方法存在用于预测体内性能的新的MRI对比剂的新MRI对比剂。当前项目的目标是开发创新的便携式设备以评估灵敏度，特异性和安全性概况使用MRI和3D微流体肿瘤模型的光学成像的Nemo颗粒与GD-螯合物的组成。我们的中心假设是Nemo颗粒将引起低毒性，特别是标记乳腺癌细胞，并产生更高的毒性与3D微流体肿瘤模型和患有乳腺癌的小鼠中的GD氯酸盐相比，MRI对比度。我们的假设将以两个目的测试：1）评估3D微流体中的Nemo粒子与GD-螯合MRI对比度肿瘤模型和小鼠。 2）评估3D微流体肿瘤模型中NEMO颗粒的毒性和分布和老鼠。该项目具有创新性，因为Nemo颗粒对内体pH的唯一反应以生成仅在乳腺癌细胞内进行对比，以提供简单的二元读数（良性“ OFF”，恶性“ ON”）。先前开发的pH敏感MRI对比剂对酸性细胞外空间有反应，这是相似的在良性和恶性肿瘤中。我们还将创建一个新型设备，以实现3D微流体肿瘤的MRI 第一次模型。拟议的研究很重要，因为我们将证明Nemo颗粒与GD螯合物相比，具有优异的特异性，信号强度和安全性。该R15奖将提供挑战 - 西弗吉尼亚大学的纳米材料和医学成像研究的本科生的边缘培训。在3年的时间里，将招募，培训，培训，培训，培训，攻读工程或生物医学科学学位的6名本科生并评估。这项工作将导致进一步的临床前开发和NEMO颗粒的临床试验。