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

肿瘤靶向 pH 敏感氧化锰纳米颗粒用于增强 MRI 乳腺癌检测

基本信息

批准号：
10709272
负责人：
Margaret Bennewitz
金额：
$ 23.78万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709272
关键词：
Address Anxiety Behavior Benign Biodistribution Biopsy Blood Blood Circulation Blood Platelets Brain Breast Cancer Cell Breast Cancer Detection Breast Cancer Early Detection Breast Cancer Model Breast Carcinoma Breast Magnetic Resonance Imaging Cancer Detection Cancerous Cardiac Cell Communication Cells Clinical Clinical Trials Complex Analysis Contrast Media Coupled DNA Data Diagnosis Drug Kinetics Early Diagnosis Encapsulated Endosomes Endothelial Cells Endothelium Ensure Exposure to Extracellular Space Fiber Future Gadolinium Goals Hepatic Human Implant Label Leukocytes Liver Lung MRI Scans Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Mammary Gland Parenchyma Mammary Neoplasms Mammography Measures Medical Care Costs Metals Modality Motor Mucin 1 protein Mus Normal tissue morphology Operative Surgical Procedures Outcome Pain Peptides Performance Property Research Resolution Safety Screening procedure Sensory Signal Transduction Skin Techniques Testing Time Toxic effect Visualization Woman Work behavior change behavior test bone cancer cell chelation clinical translation cytokine efficacy testing extracellular fluorescence imaging follow-up imaging detection improved in vivo innovation intravital fluorescence microscopy intravital microscopy malignant breast neoplasm mammary manganese oxide mouse model multimodality nano nanomaterials nanoparticle nanoscale neoplastic cell neutrophil novel optical imaging overexpression particle patient derived xenograft model supplemental screening theranostics tumor tumor microenvironment uptake young woman

项目摘要

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.

项目摘要 - 用于增强乳房的肿瘤靶向 pH 敏感氧化锰纳米颗粒使用 MRI 检测癌症对于乳腺组织致密的年轻女性来说，乳腺癌筛查的误诊率很高。这些女性接受不必要的后续测试，包括痛苦的活检、增加的焦虑和与乳房X光检查相比，磁共振成像（MRI）可以检测到更多的乳房。由于临床上使用的造影剂，例如钆 (Gd)-，癌症仍存在较高的假阳性率我们的长期目标是开发新型、安全的造影剂，用于乳腺癌的早期检测。减少乳腺 MRI 的假阳性和假阴性结果。它们缺乏靶向性和恒定的 MRI 信号，可以突出显示良性和恶性肿瘤，并且由于正常组织中产生的高背景信号而实现较低的对比度，以解决我们的长期问题。为了实现这一目标，我们开发了纳米封装氧化锰 (NEMO) 颗粒作为 Gd- 的优质替代品我们的初步数据表明，我们已经成功用靶向肽修饰 NEMO 颗粒。糖基化不足的粘蛋白-1 (uMUC-1)，仅在乳腺癌细胞上过表达，以确保 NEMO 颗粒被癌细胞摄取到酸性内体 (pH 5) 后，会产生独特的 pH- 可切换信号在血液 pH 值 (pH 7.4) 和肿瘤细胞外空间 (pH 6.5) 下产生。 NEMO 颗粒比 Gd 螯合物产生更强的信号，并且在体内可以安全耐受，有必要进行测试。通过 MRI 观察造影剂的功效；然而，MRI 无法检测小尺寸纳米颗粒多细胞因此，当前项目的目标是应用一种新颖的、集成的 MRI 方法。通过手术植入窗口的技术进行活体荧光成像小鼠乳腺肿瘤的长期可视化，将 MRI 信号与荧光纳米颗粒细胞关联起来我们追求 NEMO 颗粒能够选择性地标记乳腺癌细胞，产生更高的 MRI。相比之下，与传统的 Gd 螯合物相比，在乳腺癌小鼠模型中引起的毒性较低。目标如下：（1）确定乳腺癌模型中 NEMO 粒子 MRI 信号的敏感性和选择性， (2) 通过光学成像评估肿瘤微环境中的 NEMO 颗粒-细胞相互作用，以及 (3) 评估 NEMO颗粒在体内的安全性和药代动力学研究该项目主要有三个创新点：第一， uMUC-1靶向NEMO颗粒将仅在乳腺癌细胞中产生对比，以产生简单的二元其次，我们将开发一种新型 MRI 兼容的活体窗口以进行读出。评估乳腺肿瘤中的实时动态纳米颗粒-细胞相互作用。第三，我们将测试尚未探索的。人体血液和小鼠模型中血管内造影剂的安全机制。意义重大，因为改进的 MRI 造影剂将加速、简化和增强乳腺癌 MRI 诊断。我们的多模式平台将适用于其他癌症，并将为评估 MRI 提供新方向这项工作将导致未来 NEMO 颗粒用于增强癌症检测的临床试验。