Quantitative Monitoring and Control of Tumor Vascular Permeability in vivo Using

描述(申请人提供)：使用微泡造影剂在体内定量监测和控制肿瘤血管通透性概述：本项目的目标是开发一种新的图像引导方法，通过在体内同时监测和控制肿瘤血管通透性(VP)来优化转移性神经母细胞瘤患者的化疗治疗。神经母细胞瘤是一种侵袭性实体瘤，占儿童癌症相关死亡率的10%。与许多肿瘤不同的是，神经母细胞瘤表现出较差的血管灌注率，以防止药物外渗和靶向恶性肿瘤组织。为了治疗转移性神经母细胞瘤，使用了大剂量的化疗，这对青少年患者有有害的短期和长期副作用。为了提高化疗活性和降低治疗所需的剂量，需要采用靶点给药的方法。在这项研究中，我们提出了一种使用新型微泡造影剂(MCA)和超声(US)成像来监测和空间控制神经母细胞瘤(NGP)肿瘤中药物渗透性的方法。大脑中动脉是充满气体的球体(直径1-10？m)，比周围的血液和组织更有效地散射超声波，使临床超声扫描仪可以检测到它们。此外，当施加特定的超声波能量时，大脑中动脉在美国场中的物理反应可以产生足够的力来渗透血管系统。这项技术被称为“声波手术”，经常被用于实验室测试，以增强对肿瘤的部位特异性药物输送。因此，MCA可用于同时控制VP和监测肿瘤组织的血液灌注量的变化。目前，还没有临床方法来监测体内声学造影术的效果。在这项研究中，我们将证明大脑中动脉增强的超声成像可以用来量化与超声手术相关的血管变化。大脑中动脉是一种纯粹监测血液灌流的血管制剂。与其他体内成像造影剂不同的是，MCA太大了，无法渗入组织。然而，大量研究表明，组织的VP与血液灌流动力学之间存在很强的相关性。我们的初步数据表明，大脑中动脉血流动力学与血管正常化的定性指标相关(BV治疗--导致灌注量增加和VP增加)。因此，我们假设大脑中动脉血流动力学也可以有效地用于监测与声学治疗相关的肿瘤VP的变化。接下来，我们将应用这项技术在神经母细胞瘤肿瘤模型(NGP肿瘤)中展示可控的药物摄取，这些肿瘤表现出不同的血管形态。组织中的药物摄取主要受总血液灌注量和肿瘤血管通透性的控制，这两个因素都可以用大脑中动脉增强的超声成像来测量。因此，我们假设大脑中动脉血流动力学可用于维持给药药物的剂量对称性。这项技术对于纵向药物治疗特别相关，在纵向药物治疗中，肿瘤血管会随着治疗而动态变化。

DESCRIPTION (provided by applicant): Quantitative Monitoring and Control of Tumor Vascular Permeability In Vivo using Microbubble Contrast Agents Summary: The goal of this project is to develop a novel image-guided method of optimizing chemotherapeutic therapies in metastatic neuroblastoma patients by simultaneously monitoring and controlling tumor vascular permeability (VP) in vivo. Neuroblastomas are aggressive solid tumors responsible for 10% of childhood cancer related mortalities. Unlike many tumors, neuroblastomas exhibit poor vasculature perfusion that prevents drug extravasation and targeting of malignant tumor tissue. In order to treat metastatic neuroblastomas, high-dosage chemotherapy is used, which can have deleterious short and long-term side effects in juvenile patients. Methods of site-specific drug delivery to tumors are needed to enhance chemotherapeutic activity and lower required dosages for treatment. In this study, we propose a method of monitoring and spatially controlling drug permeability in neuroblastoma (NGP) tumors using novel microbubble contrast agents (MCA's) and ultrasound (US) imaging. MCA's are gas- filled spheres (1-10 ¿m in diameter) that scatter US waves more effectively than surrounding blood and tissue, making them detectable with clinical US scanners. Additionally, when specific ultrasonic energy is applied, the physical response of MCA's in an US field can produce enough force to permeabilize the vasculature. This technique, known as "sonoporation", is frequently utilized in laboratory testing to enhance site-specific drug delivery to tumors. Therefore, MCA's can be used to simultaneously control VP and monitor changes in blood perfusion specifically in tumor tissue. Currently, no clinical methods exist to monitor the effects of sonoporation in vivo. In this study, we will demonstrate that MCA enhanced US imaging can be used quantify vascular changes associated with sonoporation. MCA's are vascular agents that purely monitor blood perfusion. Unlike other in vivo imaging contrast agents, MCA's are too large to extravasate into tissue. However, numerous studies have demonstrated a strong correlation between VP of tissue and blood perfusion dynamics. Our preliminary data suggests that MCA perfusion dynamics correlates with qualitative indices of vascular normalization in reponse to anti-VEGF treatment (BV therapy- results in increased perfusion and VP). Therefore, we hypothesize that MCA perfusion dynamics can effectively be used to monitor changes in tumor VP associated with sonoporation as well. Next, we will apply this technique to demonstrate controlled drug uptake in neruoblastoma tumor models (NGP tumors) that exhibit varying vascular morphologies. Drug uptake in tissue is governed primarily by total blood perfusion and tumor vascular permeability, both of which can be measured using MCA enhanced US imaging. Therefore, we hypothesize that MCA perfusion dynamics can be used to maintain dose-symmetry of administered drugs. This technique would be particularly relevant for longitudinal drug therapies where the tumor vasculature is dynamically changing in response to treatment.