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

项目总结-肿瘤靶向pH敏感的氧化锰纳米颗粒用于增强乳房 使用MRI的癌症检测 乳腺癌筛查被患有致密乳腺组织的年轻女性的高误诊率所困扰。 这些妇女受到不必要的后续测试，包括痛苦的活检，增加焦虑， 更高的医疗费用。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）- 螯合物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。Gd-螯合物的不良性能由以下原因导致： 缺乏针对性和持续的核磁共振信号Gd螯合物突出良性和恶性肿瘤， 由于在正常组织中产生的高背景信号而实现较低的对比度。为了解决我们的长期 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-的上级替代品。 螯合物我们的初步数据显示，我们已经成功地用一种肽修饰了NEMO颗粒， 低糖基化粘蛋白-1（uMUC-1），其仅在乳腺癌细胞上过表达，以确保 选择性在被癌细胞摄取到酸性内体（pH 5）中后，NEMO颗粒产生独特的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）产生最小信号。 NEMO颗粒产生比Gd螯合物更强的信号，并且在体内安全耐受。必须测试 通过MRI检查造影剂的有效性;然而，MRI无法检测小规模的纳米颗粒-多细胞 实时互动。因此，当前项目的目标是应用一种新的、综合的MRI方法 和活体荧光成像，通过一种技术，该技术结合了手术植入的窗口， 小鼠乳腺肿瘤的长期可视化，以将MRI信号与荧光纳米颗粒细胞相关联 动力学我们假设NEMO颗粒将选择性地标记乳腺癌细胞，产生更高的MRI 与常规Gd螯合物相比，在乳腺癌小鼠模型中引起低毒性。我们提出 以下目的：（1）确定NEMO粒子MRI信号在乳腺癌模型中的灵敏度和选择性， (2)利用光学成像评估肿瘤微环境中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。该项目主要有三个创新点：第一， 靶向uMUC-1的NEMO颗粒将仅在乳腺癌细胞中产生对比，以产生简单的二元 读数（良性“OFF”，恶性“ON”）。其次，我们将开发一种新的MRI兼容活体窗口， 评估乳腺肿瘤中实时动态纳米颗粒-细胞相互作用。第三，我们将测试未开发 人血液和小鼠模型中的血管内造影剂安全性机制。拟议的研究是 这是非常重要的，因为改进的MRI造影剂将加快、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提供新的方向 治疗诊断剂这项工作将导致NEMO颗粒用于增强癌症检测的未来临床试验。

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.