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：
10487424
负责人：
Margaret Bennewitz
金额：
$ 21.29万
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/10487424
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.

全球每年约有 210 万女性被诊断患有乳腺癌 626,000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，尽管接受治疗，仍具有最大的转移和复发潜力。我们的长期目标是发展用于增强 TNBC 复发早期检测的创新造影剂，将大大减少误报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 光检查能检测到更多的乳腺癌；然而，假由于使用标准造影剂（例如钆螯合物），MRI 的阳性诊断率仍然很高。钆螯合物是非靶向 MRI 造影剂，总是产生信号，这导致无法准确区分良性肿瘤和恶性肿瘤。我们的方法截然不同。在此处，我们将开发新型肿瘤靶向 pH 可激活氧化锰 (MnO) 纳米颗粒 (NP)，用于早期治疗以及特定乳腺癌MRI检测。 MnO NPs 呈现出一种靶向肽，可结合糖基化不足的粘蛋白-1 (uMUC-1) 在乳腺癌细胞上过表达。 MnO NPs将被内吞特异性地被癌细胞溶解并溶解在低 pH 内体中，释放 Mn2+ 离子以启动 MRI 信号。与传统 MRI 不同，我们的靶向 MnO 纳米颗粒将专门检测恶性肿瘤，但不能检测良性肿瘤肿瘤，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 Mn2+ 比 Mn2+ 具有更高的弛豫率钆螯合物和纳米颗粒可以将更多的 Mn2+ 输送到癌症部位。由于早期诊断和及时通过我们的检测策略进行治疗，患者的生存率将显着提高。我们假设 uMUC-1 靶向 pH 可激活的 MnO NPs 将特异性标记恶性乳腺体内表达 uMUC-1 的肿瘤并产生足够的 MRI 对比度以可视化比常规钆螯合物。我们将通过以下目标来检验这一假设：1）有针对性的设计 pH可激活的MnO NPs优先在体内表达uMUC-1的TNBC肿瘤内积累。 2）确定目标 MnO NP 的毒性程度和生物分布。 3) 确定目标 pH 激活的潜力与 Multi Hance 相比，MnO NP 用于检测较小的 TNBC 肿瘤。