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

项目摘要-肿瘤靶向pH敏感纳米氧化锰乳房增强剂 利用核磁共振技术进行癌症检测 对于乳房组织致密的年轻女性来说，乳腺癌筛查的误诊率很高。 这些妇女接受了不必要的后续测试，包括痛苦的活组织检查，焦虑增加，以及 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 然而，由于临床上使用的造影剂，例如Gd(Gd)，癌症的假阳性率很高。 络合物。我们的长期目标是开发新的、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-螯合物性能不佳的原因是 他们缺乏靶向性和稳定的核磁共振信号。Gd-螯合物突出了良性肿瘤和恶性肿瘤 由于正常组织中产生的背景信号较高，因此实现较低的对比度。为了解决我们的长期问题 为了实现这一目标，我们开发了纳米包裹的氧化锰(NEMO)颗粒，作为Gd-Ne的优良替代物。 络合物。我们的初步数据显示，我们已经成功地用一种靶向NEMO的多肽修饰了NEMO颗粒 糖基化不足的粘蛋白-1(UMUC-1)，它只在乳腺癌细胞上过度表达，以确保 选择性。当癌细胞摄取到酸性内体(PH 5)时，NEMO颗粒产生一种独特的pH- 可切换信号。在血液pH值(pH 7.4)和肿瘤细胞外间隙(pH 6.5)时产生的信号最小。 尼莫颗粒与Gd-螯合物相比产生了更强的信号，并且在体内可以安全地耐受。有必要测试一下 磁共振成像对比剂的有效性；然而，磁共振成像不能检测到小尺度的纳米颗粒-多细胞 实时交互。因此，当前项目的目标是应用一种新颖的、集成的核磁共振方法 通过一种技术进行活体内荧光成像，该技术结合了一种通过外科手术植入的窗口 长期观察小鼠乳腺肿瘤MRI信号与荧光纳米细胞的关系 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 与传统的Gd-螯合物相比，该药物在乳腺癌小鼠模型中的毒性较低。我们建议 目的：(1)确定NEMO颗粒MRI信号在乳腺癌模型中的敏感性和选择性， (2)用光学成像技术评价肿瘤微环境中NEMO颗粒与细胞的相互作用；(3)评价NEMO颗粒与细胞的相互作用 尼莫微粒在体内的安全性和药代动力学。该项目主要有三个创新：一是， UMUC-1靶向NEMO颗粒只会在乳腺癌细胞中产生对比度，从而产生简单的二元 读数(良性“关”，恶性“开”)。其次，我们将开发一种新的MRI兼容的活体内窗口 评价乳腺肿瘤中纳米粒子与细胞的实时动态相互作用。第三，我们将测试未探索的 血管内造影剂在人类血液和小鼠模型中的安全性机制。拟议的研究是 重要的是，改进的MRI造影剂将加快、简化和增强乳腺癌的MRI诊断。 我们的多模式平台将适用于其他癌症，并将在评估MRI方面提供新的方向 治疗用麻醉剂。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.