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

肿瘤血管通透性大小依赖的定量成像技术 (即，在宏观到纳米尺寸范围内)具有极大的临床意义。这些技术将是非常有用的 让肿瘤学家评估肿瘤血管对不同大小药物的渗透性，并根据药物 无障碍，对患者分层进行适当治疗。此外，它还可以用来监测肿瘤 对任何可能调节肿瘤血管通透性和改善肿瘤血管通透性的干预措施的反应 药物递送。在目前的应用中，我们建议直接使用高度安全的、临床可用的右旋糖苷 作为一种新的磁共振成像探针，无需任何放射性就可以评估肿瘤血管的渗透性， 顺磁性或超顺磁性标签。在这种方法中，右旋糖苷是通过其可交换的 使用最新出现的磁共振成像对比机制--化学交换饱和--的羟基(OH)质子 转移(CEST)，即葡聚糖增强型CEST(DexCEST)。因为右旋糖苷的供应范围很广 颗粒大小--分子量(MW)从10kD到2MD分别从5 nm到54 nm，因此 在广泛的应用中，将它们用作宏纳米尺寸的磁共振成像剂是可行的。因此，我们 假设dexCEST MRI可以用来评估大小依赖的肿瘤血管通透性，并 监测胰腺癌肿瘤血管通透性对间质靶向治疗的反应。在……里面 特别是，我们将首先充分优化和验证dexCEST MRI检测，以评估大小依赖的肿瘤 实验性胰腺导管腺癌肿瘤的血管通透性。然后，我们将使用这个 监测实验性PDAC肿瘤对间质靶向治疗的肿瘤反应的技术，这将 导致对使用dexCEST MRI作为成像生物标记物量化治疗效果的评估 基质耗竭药物。这一项目的顺利完成将立即对 基质靶向治疗低通透性的临床前研究进展及临床应用 PDAC以个性化的医疗方式。因为许多新药都在大尺寸范围内(即单克隆 抗体)和纳米范围(纳米医学)，我们的方法有望在 新开发的化疗和免疫治疗及其联合应用的临床应用 基质靶向疗法。此外，我们预计这些开发可以很容易地针对其他类型进行调整 实体瘤的症状。

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.