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：
10246798
负责人：
Margaret Bennewitz
金额：
$ 21.31万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246798
关键词：
3-Dimensional Anxiety Benign Binding Biodistribution Biopsy Breast Cancer Cell Breast Cancer Detection Cancer Model Cardiac Cells Chelating Agents Contrast Media Detection Diagnosis Drug Kinetics Early Diagnosis Endosomes Gadolinium Goals Gold Hepatic Human Image Imaging Techniques Implant In Vitro Injections Ions Label MDA MB 231 Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammography Measures Medical Microfluidic Microchips Mucin 1 protein MultiHance Mus Neoplasm Metastasis Operative Surgical Procedures Patients Peptides Sepharose Signal Transduction Testing Time Toxic effect Woman breast imaging cancer cell cancer recurrence cancer site contrast imaging cytotoxicity design detection sensitivity imaging detection in vivo innovation knock-down malignant breast neoplasm manganese oxide nanoparticle novel overexpression particle small hairpin RNA triple-negative invasive breast carcinoma tumor tumor microenvironment uptake

项目摘要

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.

全球约有210万妇女将每年诊断出患有乳腺癌 626,000名妇女会因此而死。三重阴性乳腺癌（TNBC）是最具侵略性的亚型，尽管有治疗，但具有转移和复发的最大潜力。我们的长期目标是发展创新的对比剂，以增强对TNBC复发的早期检测，这将大大减少错误与当前的乳房成像技术相关的负面因素和假阳性。磁共振成像（MRI）比乳房X线摄影检测到更多的乳腺癌。但是，错误由于所使用的标准对比剂（例如，螯合物），阳性诊断的阳性诊断仍然很高。螯合物是未靶向的MRI对比剂，总是会产生信号，这导致无法准确区分良性与恶性肿瘤。我们的方法截然不同。在此处，我们将在早期开发新型的以肿瘤靶向的pH-活化锰氧化物（MNO）纳米颗粒（NP）和特定的乳腺癌MRI检测。 MNO NP提出了一种靶向肽，该肽与在乳腺癌细胞上过表达的糖基化粘蛋白-1（UMUC-1）。 MNO NP将被内吞特别是通过癌细胞并溶解在低pH内体中以释放MN2+离子以启动MRI信号。与常规MRI不同，我们的目标MNO NP会特别检测到恶性肿瘤，但不能检测到良性肿瘤，因为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，进一步的成像，焦虑，并节省多达30亿美元的医疗费用每年。此外，MNO NP可以促进较小肿瘤的检测，因为MN2+的松弛性比螯合物和NP可以为癌症部位提供更多的MN2+。由于较早的诊断和提示通过我们的检测策略实现了治疗，患者生存将显着增加。我们假设UMUC-1靶向pH-活化的MNO NP会特异性标记恶性乳房在体内表达UMUC-1的肿瘤并产生与可视化较小肿瘤相比的足够的MRI对比常规的螯合物。我们将以以下目的检验该假设：1）设计针对可pH-激活的MNO NP优先积聚在体内表达UMUC-1的TNBC肿瘤中。 2）确定靶向MNO NP的毒性程度和生物分布。 3）确定靶向性脱位的潜力与多hance相比，用于检测较小的TNBC肿瘤的MNO NP。