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.

定量成像技术，用于表征大小依赖性肿瘤血管通透性 （即，在宏观到纳米范围内）具有极大的临床感兴趣。这样的技术将非常有用 肿瘤学家评估肿瘤血管渗透性对不同尺寸的药物，并基于药物 可访问性，以对患者进行适当的治疗进行分层。此外，它可用于监测肿瘤 对任何可能调节肿瘤血管通透性并改善的干预措施的反应 药物输送。在当前的应用程序中，我们建议直接使用高度安全的临床上可用的葡萄糖 作为用于评估肿瘤血管通透性的新的MRI探针，而无需任何放射性， 顺磁性或超顺磁性标签。在这种方法中，Dextran可直接通过其可交换 羟基（OH）质子使用最近出现的MRI对比机制，化学交换饱和度 转移（CEST），即右旋增强的Cest（Dexcest）。因为葡萄糖范围内可用 粒径的分子量（MW）分别从5到54 nm，分别为10 kd至2 MD，因此是 在广泛的应用中，可以将它们用作宏观和纳米大小的MR成像剂。因此，我们 假设Dexcest MRI可用于评估依赖大小的肿瘤血管通透性，并 监测胰腺癌对基质靶向疗法的肿瘤血管通透性的反应。在 特别是，我们将首先完全优化和验证Dexcest MRI检测以评估尺寸依赖性肿瘤 实验性胰腺导管腺癌（PDAC）肿瘤的血管通透性。然后，我们将使用此 监测实验性PDAC肿瘤中对基质靶向疗法的肿瘤反应的技术，该疗法将 导致评估使用右键MRI作为成像生物标志物的使用来量化的疗效 缺乏基质的药物。该项目的成功完成将立即影响 临床前开发和临床实施靶向基质的疗法，以治疗不可渗透性 PDAC以个性化医学方式。因为许多新药在宏观范围内（即单春 抗体）和纳米大小范围（纳米医学），我们的方法有望在 新开发的化学疗法和免疫疗法的临床实施，以及它们与 靶向基质的疗法。此外，我们期望这些发展可以轻松量身定制为其他类型 实体瘤。