Quantitative Monitoring and Control of Tumor Vascular Permeability in vivo Using

体内肿瘤血管通透性的定量监测和控制

• 批准号: 8385482
• 负责人: Mark Andrew Borden
• 金额: $ 19.79万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385482
• 关键词: Address; Adolescent; Adverse effects; Aftercare; Area; Blood; Blood Vessels; Blood capillaries; Caliber; Cancer Model; Cell Survival; Child; Clinical; Contrast Media; Data; Dose; Doxorubicin; Drug Controls; Drug Delivery Systems; Drug Extravasation; Exhibits; Extravasation; Frequencies; Gases; Goals; Hematocrit procedure; Heterogeneity; High Dose Chemotherapy; Hour; Image; Immunohistochemistry; Individual; Injection of therapeutic agent; Laboratories; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Methods; Microbubbles; Modeling; Monitor; Morphology; Mus; Neuroblastoma; Patients; Perfusion; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Property; Resistance; Site; Solid Neoplasm; Staging; Structure; Techniques; Testing; Tissues; Treatment Efficacy; Tumor Tissue; Ultrasonic Therapy; Ultrasonic wave; Ultrasonics; Ultrasonography; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; bevacizumab; blood perfusion; capillary; chemotherapy; clinical practice; clinically relevant; design; dosage; fluorescein isothiocyanate dextran; in vivo; indexing; insight; matrigel; mortality; novel; plasmid DNA; prevent; response; sonoporation; tumor; tumor growth; uptake

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. PUBLIC HEALTH RELEVANCE: This project is designed to address a fundamental need to develop clinically relevant techniques for monitoring and controlling drug permeability in chemoresistant tumors. In clinical practice, it is impossible to predict a priori whether an individual patient will respond to a specific treatment regime. Instead, an optimized treatment must be judiciously selected based on the known perfusion properties of the tumor, then dynamically altered over the course of treatment to reflect the tumor response. The techniques proposed in this study can (1) provide insight into tumor vascular properties (2) monitor dynamic changes in the tumor vasculature in response to treatment, and (3) alter the vascular structure to optimize treatment efficacy. The results of this study will serve to demonstrate that contrast-enhanced ultrasound imaging and sonoporation is a rational and clinically relevant approach to optimizing chemotherapeutic activity in neuroblastomas as well as other chemoresistant cancer models.

描述（由申请人提供）：使用微泡造影剂定量监测和控制体内肿瘤血管通透性 总结：该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体内肿瘤血管通透性（VP）来优化转移性神经母细胞瘤患者的化疗。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，神经母细胞瘤表现出不良的脉管系统灌注，这阻止了药物外渗和恶性肿瘤组织的靶向。为了治疗转移性神经母细胞瘤，使用高剂量化疗，这在青少年患者中可能具有有害的短期和长期副作用。需要向肿瘤的位点特异性药物递送的方法来增强化疗活性并降低治疗所需的剂量。在这项研究中，我们提出了一种方法，监测和空间控制药物渗透性神经母细胞瘤（NGP）肿瘤使用新的微泡造影剂（MCA的）和超声（US）成像。MCA是充满气体的球体（直径1-10 μ m），比周围的血液和组织更有效地散射US波，使其能够被临床US扫描仪检测到。此外，当施加特定的超声能量时，MCA在US场中的物理响应可以产生足够的力来透化脉管系统。这种技术被称为“声致穿孔”，经常用于实验室测试，以增强向肿瘤的位点特异性药物递送。因此，MCA可用于同时控制VP和监测肿瘤组织中血液灌注的变化。目前，还没有临床方法来监测体内声孔效应。在这项研究中，我们将证明，MCA增强的US成像可以用来量化与声孔相关的血管变化。MCA是纯粹监测血液灌注的血管剂。与其他体内成像造影剂不同，MCA太大而不能外渗到组织中。然而，许多研究已经证明了组织VP和血液灌注动力学之间的强相关性。我们的初步数据表明，MCA灌注动力学与抗VEGF治疗（BV治疗-导致灌注和VP增加）后血管正常化的定性指标相关。因此，我们假设MCA灌注动力学也可以有效地用于监测与声孔相关的肿瘤VP的变化。接下来，我们将应用这种技术来证明控制药物摄取神经母细胞瘤肿瘤模型（NGP肿瘤），表现出不同的血管形态。组织中的药物摄取主要由总血液灌注和肿瘤血管渗透性控制，这两者都可以使用MCA增强US成像来测量。因此，我们假设MCA灌注动力学可用于维持给药药物的剂量对称性。这种技术对于肿瘤脉管系统响应于治疗而动态变化的纵向药物治疗将是特别相关的。 公共卫生关系：该项目旨在解决开发临床相关技术以监测和控制耐药肿瘤中药物渗透性的基本需求。在临床实践中，不可能先验地预测个体患者是否会对特定治疗方案作出反应。相反，必须根据肿瘤的已知灌注特性明智地选择优化的治疗，然后在治疗过程中动态地改变以反映肿瘤反应。本研究中提出的技术可以（1）提供对肿瘤血管特性的深入了解（2）监测肿瘤血管系统对治疗的动态变化，以及（3）改变血管结构以优化治疗效果。本研究的结果将证明，对比增强超声成像和声孔作用是一种合理的和临床相关的方法，以优化神经母细胞瘤以及其他化学耐药癌症模型的化疗活性。