Quantitative Monitoring and Control of Tumor Vascular Permeability in vivo Using

摘要：本项目的目标是开发一种新的图像引导方法，通过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，神经母细胞瘤表现为血管灌注不良，阻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，使用高剂量化疗，这可能对青少年患者产生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剂量，需要针对肿瘤部位的药物递送方法。在这项研究中，我们提出了一种利用新型微泡造影剂（MCA）和超声（US）成像监测和空间控制神经母细胞瘤（NGP）肿瘤药物通透性的方法。MCA是充满气体的球体（直径1-10米），它比周围的血液和组织更有效地散射美国波，使其被临床美国扫描仪检测到。此外，当施加特定的超声能量时，MCA在美国场中的物理响应可以产生足够的力来渗透血管系统。这种技术被称为“声波穿透”，经常用于实验室检测，以增强对肿瘤的部位特异性药物递送。因此，MCA可以同时用于控制VP和监测肿瘤组织血液灌注的变化。目前，还没有临床方法来监测超声穿孔在体内的效果。在这项研究中，我们将证明MCA增强的US成像可以用于量化与超声相关的血管变化。MCA是单纯监测血液灌注的血管制剂。与其他体内显像造影剂不同，MCA的体积太大，不能外溢到组织中。然而，大量研究表明组织VP与血液灌注动力学之间存在很强的相关性。我们的初步数据表明，MCA灌注动力学与抗vegf治疗后血管正常化的定性指标相关（BV治疗-导致灌注和VP增加）。因此，我们假设MCA灌注动力学也可以有效地用于监测与超声相关的肿瘤VP的变化。接下来，我们将应用这项技术来证明神经母细胞瘤肿瘤模型（NGP肿瘤）中表现出不同血管形态的药物摄取控制。组织中的药物摄取主要受总血流灌注和肿瘤血管通透性的控制，这两者都可以通过MCA增强的US成像来测量。因此，我们假设MCA灌注动力学可以用来维持给药的剂量对称性。这项技术将特别适用于纵向药物治疗，其中肿瘤血管系统是动态变化的，以响应治疗。

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.