CEST MRI assessment of tumor vascular permeability using non-labeled dextrans

使用非标记葡聚糖评估肿瘤血管通透性的 CEST MRI

• 批准号: 9297917
• 负责人: Guanshu Liu
• 金额: $ 17.58万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297917
• 关键词: Antibodies; Antineoplastic Agents; Cancer Etiology; Cessation of life; Chemicals; Clinical; Contrast Media; Data; Desmoplastic; Detection; Development; Dextrans; Drug Delivery Systems; Effectiveness; Evaluation; Human; Human Characteristics; Hyaluronidase; Hydroxyl Radical; Image; Imaging Device; Imaging technology; Immunohistochemistry; Immunotherapy; Intercellular Fluid; Intervention; Label; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mechanics; Medical Imaging; Methods; Microscopy; Mission; Molecular Weight; Monitor; Mus; Oncologist; Pancreatic Ductal Adenocarcinoma; Particle Size; Patients; Permeability; Pharmaceutical Preparations; Play; Protocols documentation; Protons; Public Health; Radioactive; Reporting; Research; Role; Safety; Sensitivity and Specificity; Signal Transduction; Solid Neoplasm; Survival Rate; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; United States; United States National Institutes of Health; Vascular Permeabilities; base; cancer type; chemotherapy; clinical application; clinical translation; contrast enhanced; gemcitabine; image guided; imaging agent; imaging biomarker; imaging potential; immune checkpoint blockade; improved; innovation; interest; method development; mouse model; nanomedicine; nanoparticulate; nanosized; non-invasive imaging; novel therapeutics; outcome forecast; pancreatic neoplasm; patient stratification; personalized medicine; preclinical development; pressure; quantitative imaging; response; targeted agent; targeted treatment; therapy outcome; tumor; two-photon

Quantitative imaging technologies for the characterization of the size-dependent tumor vascular permeability (i.e., in the macro- to nano- size range) are of great clinical interest. Such technologies will be extremely useful for oncologists to assess the tumor vascular permeability to drugs at different sizes and, based on the drug accessibility, to stratify patients for the appropriate treatment. Moreover it can be used to monitor the tumor responses to any interventions that can potentially modulate the tumor vascular permeability and improve the drug delivery. In the current application, we propose to directly use the highly-safe, clinically-available dextrans as new MRI probes for assessing tumor vascular permeability without the need for any radioactive, paramagnetic, or super-paramagnetic label. In this approach, dextran is detected directly via its exchangeable hydroxyl (OH) protons using a recently emerged MRI contrast mechanism, Chemical Exchange Saturation Transfer (CEST), namely dextran-enhanced CEST (dexCEST). Because dextrans are available in a wide range of particle sizes-- from 5 to 54 nm for molecular weights (MW) from 10 kD to 2 MD, respectively, it is therefore feasible to use them as macro- and nano-sized MR imaging agents in a broad range of applications. As such, we hypothesize that dexCEST MRI can be used to assess the size-dependent tumor vascular permeability, and to monitor the response in the tumor vascular permeability of pancreatic cancer to stroma-targeting therapies. In particular, we will first fully optimize and validate dexCEST MRI detection to assess size-dependent tumor vascular permeability of experimental pancreatic ductal adenocarcinoma (PDAC) tumors. Then, we will use this technique to monitor the tumor response to stroma-targeting therapies in experimental PDAC tumors, which will lead to the evaluation of the use of dexCEST MRI as an imaging biomarker to quantify the efficacy of stroma-depleting drugs. The successful completion of this project will have an immediate impact on the pre-clinical development and clinical implementation of stroma-targeting therapies to treat hypo-permeable PDAC in a personalized medicine manner. Because many new drugs are in macro-size range (i.e., monocolonal antibodies) and nano-size range (nanomedicine), our approach is expected to play an important role in the clinical implementation of newly developed chemotherapy and immunotherapy, as well as their combination with stroma-targeting therapies. In addition, we expect that these developments can be easily tailored to other types of solid tumors.

用于表征大小依赖性肿瘤血管通透性的定量成像技术 （即在宏观到纳米尺寸范围内）具有很大的临床意义。这些技术将非常有用 供肿瘤学家评估不同大小的肿瘤血管对药物的通透性，并根据药物 可及性，对患者进行分层以获得适当的治疗。此外，它还可用于监测肿瘤 对任何可能调节肿瘤血管通透性并改善肿瘤血管通透性的干预措施的反应 药物输送。在目前的应用中，我们建议直接使用安全性高、临床可用的右旋糖酐 作为新的 MRI 探针，无需任何放射性即可评估肿瘤血管通透性， 顺磁性或超顺磁性标签。在这种方法中，右旋糖酐通过其可交换性直接检测 使用最近出现的 MRI 对比机制“化学交换饱和”来检测羟基 (OH) 质子 转（CEST），即葡聚糖增强CEST（dexCEST）。因为右旋糖酐的用途很广 粒径——从 5 到 54 nm，分子量 (MW) 分别从 10 kD 到 2 MD，因此 可以在广泛的应用中将它们用作宏观和纳米尺寸的磁共振成像剂。因此，我们 假设 dexCEST MRI 可用于评估大小依赖性肿瘤血管通透性，并 监测胰腺癌肿瘤血管通透性对基质靶向治疗的反应。在 特别是，我们将首先全面优化和验证 dexCEST MRI 检测以评估大小依赖性肿瘤 实验性胰腺导管腺癌（PDAC）肿瘤的血管通透性。然后，我们将使用这个 监测实验性 PDAC 肿瘤中基质靶向治疗的肿瘤反应的技术，这将 导致使用 dexCEST MRI 作为成像生物标志物来量化疗效的评估 基质消耗药物。该项目的顺利完成将产生立竿见影的影响 治疗低渗透性基质靶向疗法的临床前开发和临床实施 PDAC 以个性化医疗方式进行。因为许多新药都处于宏观尺寸范围内（即单克隆 抗体）和纳米尺寸范围（纳米医学），我们的方法预计将在 新开发的化疗和免疫疗法及其联合治疗的临床实施 基质靶向疗法。此外，我们期望这些开发可以轻松地适应其他类型 实体瘤。