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

全球每年约有210万妇女被诊断为乳腺癌或以上 62.6万名女性将因此而死亡。三阴性乳腺癌(TNBC)是最具侵袭性的亚型， 尽管接受了治疗，但转移和复发的可能性最大。我们的长期目标是开发一种 创新的造影剂，增强了对TNBC复发的早期检测，将大大减少假性 与当前乳房成像技术相关的阴性和假阳性。 磁共振成像(MRI)比乳房X光摄影检测到更多的乳腺癌；然而，错误的 由于使用了标准的造影剂(如螯合物)，MRI的阳性诊断率仍然很高。 格拉络合物是一种非靶向核磁共振造影剂，总是会产生信号，这会导致 不能准确区分良性肿瘤和恶性肿瘤。我们的做法截然不同。在这里， 我们将开发新的肿瘤靶向的pH可激活的氧化锰纳米颗粒(NPs)，用于早期 以及特定的乳腺癌核磁共振检测。MNO纳米粒呈现一种结合于 低糖基化粘蛋白-1(UMUC-1)在乳腺癌细胞上过表达。MnO NPs将被内吞 特异性地由癌细胞和溶解在低pH值的内涵体中释放出Mn2+离子来启动磁共振信号。 与传统的核磁共振不同，我们的靶向MnO纳米粒子将专门检测恶性肿瘤，而不是良性肿瘤 肿瘤，因为UMUC-1只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30亿美元的医疗账单 每年一次。此外，MnO纳米粒子可以促进对较小肿瘤的检测，因为Mn2+具有比 格拉络合物和纳米粒子可以将更多的Mn2+输送到癌症部位。由于早期诊断和提示 通过我们的检测策略进行治疗，患者的存活率将显著提高。 我们假设UMUC-1靶向pH可激活的MnO纳米粒将特异性地标记恶性乳腺 体内表达UMUC-1的肿瘤并产生足够的MRI对比度以显示比 传统的Gd络合物。我们将通过以下目标来验证这一假设：1)有针对性的设计 PH可激活的MnO纳米粒在体内优先积聚在表达UMUC-1的TNBC肿瘤内。2) 确定靶向MnO纳米粒的毒性程度和生物分布。3)建立靶向pH可激活的潜力 与MULTHANCE相比，MNO NPS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.