Flow-based remodeling and function of tumor vasculature

基于流的肿瘤脉管系统重塑和功能

基本信息

批准号：
8064674
负责人：
LANCE L MUNN
金额：
$ 32.06万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064674
关键词：
Address Affect Aftercare Algorithms Angiogenesis Inhibitors Animals Antibodies Area Under Curve Back Biology Blood Blood Vessels Blood flow Bolus Infusion Boxing Breast Carcinoma Caliber Cell Proliferation Cells Clinical Trials Complex Computer Architectures Contracts Convection Cytotoxic agent DC101 Monoclonal Antibody Data Data Set Dextrans Diffusion Dose Doxorubicin Drug Delivery Systems Endothelial Cells Erythrocytes Extravasation Glioma Hematocrit procedure Hypoxia Image Individual Injection of therapeutic agent Kinetics Left Maintenance Maps Measurement Measures Mediating Metabolic Microscopy Modeling Morphogenesis Mus Neoplasms in Vascular Tissue Nitric Oxide Oranges Oxygen Pathway interactions Pattern Perfusion Permeability Pharmaceutical Preparations Physiology Plasma Plastics Play Process Production Resolution Role Running Signal Transduction Simulate Specific qualifier value Staging Structure System Testing Time Tissues Tracer Tumor Tissue Variant Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular remodeling Work Wound Healing base bevacizumab cancer cell cell motility dextran drug distribution improved mathematical model nanoparticle particle pressure public health relevance senescence shear stress simulation spatiotemporal success theories tissue oxygenation tumor two-photon vascular bed

项目摘要

DESCRIPTION (provided by applicant): "Normalization" of tumor blood vessels has shown promise to improve the efficacy of chemotherapeutics. In theory, anti-angiogenic drugs targeting endothelial VEGF signaling can improve vessel network structure and function, enhancing the transport of subsequent cytotoxic drugs to cancer cells. In practice, the effects are unpredictable, with varying levels of success. The predominant effects of anti-VEGF therapies are decreased vessel leakiness (hydraulic conductivity), decreased vessel diameters and pruning of the immature vessel network. It is thought that each of these can influence perfusion of the vessel network, inducing flow in regions that were previously sluggish or stagnant. Unfortunately, when anti-VEGF therapies affect vessel structure and function, the changes are dynamic and overlapping in time, and it has been difficult to identify a consistent and predictable normalization "window" during which perfusion and subsequent drug delivery is optimal. This is largely due to the non-linearity in the system, and the inability to distinguish the effects of decreased vessel leakiness from those due to network structural changes in clinical trials or animal studies. We have developed a mathematical model to calculate blood flow in complex tumor networks imaged by two- photon microscopy. The model incorporates the necessary and sufficient components for addressing the problem of normalization of tumor vasculature: i) lattice-Boltzmann calculations of the full flow field within the vasculature and within the tissue, ii) diffusion and convection of soluble species such as oxygen or drugs within vessels and the tissue domain, iii) distinct and spatially-resolved vessel hydraulic conductivities and permeabilities for each species, iv) erythrocyte particles advecting in the flow and delivering oxygen with real oxygen release kinetics, v) shear stress-mediated vascular remodeling. We propose to use this model, guided by multi-parameter intravital imaging of tumor vessel structure and function, to determine the structural and functional determinants of tumor vessel normalization. PUBLIC HEALTH RELEVANCE: Tumor blood vessels are chronically immature and unstable, but anti-angiogenic drugs can induce their morphogenesis in a process resembling adaptive remodeling in wound healing. Unfortunately little is known about how the resulting structural and functional changes affects the delivery of oxygen or drugs to the tumor. We will apply a mathematical model to determine how changes in vessel leakiness and network structure individually influence oxygen and drug delivery throughout tumor.

描述（由申请人提供）：肿瘤血管的“正常化”已显示出提高化疗效果的希望。理论上，针对内皮 VEGF 信号传导的抗血管生成药物可以改善血管网络结构和功能，增强后续细胞毒性药物向癌细胞的转运。在实践中，效果是不可预测的，成功程度也各不相同。抗 VEGF 疗法的主要作用是减少血管渗漏（水力传导性）、减小血管直径和修剪不成熟的血管网络。据认为，这些因素中的每一个都会影响血管网络的灌注，从而诱导先前缓慢或停滞的区域的血流。不幸的是，当抗VEGF疗法影响血管结构和功能时，这些变化是动态的并且在时间上重叠，并且很难确定一致且可预测的正常化“窗口”，在此期间灌注和随后的药物递送是最佳的。这主要是由于系统的非线性，以及无法区分血管渗漏减少的影响与临床试验或动物研究中网络结构变化造成的影响。我们开发了一种数学模型来计算双光子显微镜成像的复杂肿瘤网络中的血流。该模型包含了解决肿瘤脉管系统正常化问题所需的充分组件：i) 脉管系统内和组织内的全流场的格子玻尔兹曼计算，ii) 可溶物质（例如氧气或药物）的扩散和对流在血管和组织域内，iii）每个物种的独特且空间分辨的血管水力传导率和渗透率，iv）红细胞颗粒在流动中平流并以真实的速度输送氧气氧释放动力学，v) 剪切应力介导的血管重塑。我们建议使用该模型，在肿瘤血管结构和功能的多参数活体成像的指导下，确定肿瘤血管正常化的结构和功能决定因素。公共健康相关性：肿瘤血管长期不成熟且不稳定，但抗血管生成药物可以在类似于伤口愈合中适应性重塑的过程中诱导其形态发生。不幸的是，人们对由此产生的结构和功能变化如何影响氧气或药物向肿瘤的输送知之甚少。我们将应用数学模型来确定血管渗漏和网络结构的变化如何单独影响整个肿瘤的氧气和药物输送。