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

每年全球约有210万女性被诊断患有乳腺癌 626，000名女性将因此死亡。三阴性乳腺癌（TNBC）是最具侵略性的亚型， 即使治疗也有很大的转移和复发的可能性。我们的长期目标是发展一个 用于增强TNBC复发的早期检测的创新造影剂，将大大降低假阳性率。 与当前乳腺成像技术相关的阴性和假阳性。 磁共振成像（MRI）比乳房X光检查检测出更多的乳腺癌;然而， 由于使用的标准造影剂（例如钆螯合物），MRI的阳性诊断仍然很高。 钆螯合物是非靶向MRI造影剂，其总是产生信号，这导致 无法准确区分良性和恶性肿瘤。我们的方法完全不同。在此， 我们将开发新的肿瘤靶向pH可激活的氧化锰（MnO）纳米颗粒（NPs），用于早期 和特异性乳腺癌MRI检测。MnO NPs呈现结合至MnO NPs的靶向肽。 在乳腺癌细胞上过表达的低糖基化粘蛋白-1（uMUC-1）。MnO NPs将被内吞 特别是通过癌细胞并且溶解在低pH内体中以释放Mn 2+离子来引发MRI信号。 与常规MRI不同，我们的靶向MnO NPs将特异性检测恶性肿瘤，但不能检测良性肿瘤。 uMUC-1仅存在于乳腺癌细胞上。通过减少误报，我们的方法将 避免不必要的活检，手术，进一步成像，焦虑，并节省高达30亿美元的医疗费用 每年。此外，MnO NPs可以促进较小肿瘤的检测，因为Mn 2+具有比Mn 2+更高的弛豫率。 钆螯合物和NP可以将更多的Mn 2+递送到癌症部位。由于早期诊断和及时 通过我们的检测策略，患者的生存率将显著提高。 我们假设uMUC-1靶向的pH可激活MnO纳米颗粒将特异性标记恶性乳腺癌， 在体内表达uMUC-1的肿瘤，并产生足够的MRI对比，以显示比 常规钆螯合物。我们将测试这一假设与以下目标：1）设计目标 pH-可活化MnO NP优先在体内表达uMUC-1的TNBC肿瘤内积累。（二） 确定目标MnO NP的毒性程度和生物分布。3)确定靶向pH可激活的可能性 与Multi Hance相比，MnO NP用于检测较小的TNBC肿瘤。

Approximately 2.1 million women globally will be diagnosed with breast cancer each year and over 626,000 women will die because of it. Triple negative breast cancer (TNBC) is the most aggressive subtype, with the greatest potential to metastasize and recur despite treatment. Our long-term goal is to develop an innovative contrast agent for enhanced early detection of TNBC recurrence that will greatly reduce the false negatives and false positives associated with current breast imaging techniques. Magnetic resonance imaging (MRI) detects more breast cancers than mammography; however, false positive diagnoses remain high with MRI due to the standard contrast agent used (e.g. gadolinium chelate). Gadolinium chelates are non-targeted MRI contrast agents that always generate signal, which leads to the inability to accurately distinguish benign from malignant tumors. Our approach is drastically different. Herein, we will develop novel tumor-targeted pH-activatable manganese oxide (MnO) nanoparticles (NPs) for early and specific breast cancer MRI detection. MnO NPs present a targeting peptide that binds to underglycosylated mucin-1 (uMUC-1) overexpressed on breast cancer cells. MnO NPs will be endocytosed specifically by cancer cells and dissolved in low pH endosomes to release Mn2+ ions to initiate MRI signal. Unlike conventional MRI, our targeted MnO NPs will specifically detect malignant tumors but not benign tumors, as uMUC-1 is only present on breast cancer cells. By reducing false positives, our approach will avoid unnecessary biopsies, surgery, further imaging, anxiety, and save up to $3 billion in medical bills annually. In addition, MnO NPs can promote detection of smaller tumors, as Mn2+ has higher relaxivity than gadolinium chelates and NPs can deliver more Mn2+ to the cancer site. Due to earlier diagnosis and prompt treatment enabled with our detection strategy, patient survival will be significantly increased. We hypothesize that uMUC-1 targeted pH-activatable MnO NPs will specifically label malignant breast tumors expressing uMUC-1 in vivo and produce sufficient MRI contrast to visualize smaller tumors than conventional gadolinium chelates. We will test this hypothesis with the following aims: 1) Design targeted pH-activatable MnO NPs to preferentially accumulate within TNBC tumors expressing uMUC-1 in vivo. 2) Determine degree of toxicity and biodistribution of targeted MnO NPs. 3) Establish potential of targeted pHactivatable MnO NPs for detecting smaller TNBC tumors compared to Multi Hance.