Assessing vascular permeability and nanobubble extravasation with contrast-enhanced ultrasound imaging

通过对比增强超声成像评估血管通透性和纳米气泡外渗

基本信息

批准号：
10543043
负责人：
Michaela Cooley
金额：
$ 5.21万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543043
关键词：
Acoustics Adsorption Affect Architecture Atherosclerosis Behavior Biological Markers Blood Blood Cells Blood Vessels Bradykinin Cell surface Characteristics Chick Embryo Chronic Circulation Clinical Contrast Media Controlled Environment Data Development Diabetes Mellitus Diameter Disease Dose Embryo Endothelial Cells Endothelium Ensure Environment Erythrocytes Exposure to Extracellular Matrix Extravasation Flow Cytometry Foundations Goals Growth Factor Health Care Costs Heme Histamine Histology Human Image Imaging Techniques Immune system In Vitro Individual Inflammation Inflammatory Injections Kinetics Knowledge Location Malignant Neoplasms Measures Methods Microbubbles Microfluidic Microchips Microscopy Monitor Morphology Movement Normal tissue morphology Pancreas Pathologic Patient Care Patients Permeability Pharmaceutical Preparations Physiological Probability Process Production Protocols documentation Regimen Research Retinal Diseases Selection for Treatments Site Solid Neoplasm Structure Surface Testing Therapeutic Therapeutic Intervention Time Tissues Translations Treatment Efficacy Tumor Tissue Ultrasonography Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Permeabilities Whole Blood Work angiogenesis chorioallantoic membrane chronic inflammatory disease contrast enhanced cost effective cytokine diabetic experimental study imaging modality improved in vivo in vivo imaging individual patient membrane model mouse model nanobubble nanoparticle nanoparticle delivery nanoscale nanosized nanotherapeutic novel particle personalized therapeutic predictive tools real-time images side effect soft tissue spatiotemporal subcutaneous time interval tool tumor ultrasound uptake

项目摘要

PROJECT SUMMARY In many chronic inflammatory diseases, vascular endothelial cells become pathologically permeable due to conditions like angiogenesis and production of growth factors and inflammatory cytokines (e.g. histamine, bradykinin, etc.). In cancer, this process can be exploited for delivery of nanoparticles to tumors via the enhanced permeability and retention (EPR) effect. However, nanoparticle-based therapeutics have led to inconsistent results in patients. This is due to many factors, with a main one being heterogeneous tumor vascular architecture both between patients and within a single tumor. Transport of the nanoparticle to the tumor and into the parenchyma is complicated by uptake by the immune system, ineffective margination, and inefficient extravasation. Guidance is needed to inform clinicians on what therapies may be most effective for each patient. Effective guidance could reduce health-care costs and negative side effects of medication. An inexpensive, safe, non-invasive, and real-time imaging method may be capable of categorizing the extent of vascular permeability in tumors and once validated, personalize therapeutic regimens for patients. Such a tool could be used not only for tumors, but for all diseases involving pathologically permeable vasculature. With this goal in mind, the objective of the proposed research in this application is to work toward development of a real-time method for evaluating vascular permeability over the entire tumor using novel nanobubble (NB)-based contrast-enhanced ultrasound (CEUS) in vivo. This method will build upon dynamic CEUS protocols used clinically with microbubbles (MBs). NBs, which are 100-400 nm in diameter, have been shown to extravasate into the tumor parenchyma. The use of clinical ultrasound in developing this method will ensure that eventual translation to patients is safe, cost-effective, non-invasive, and widely accessible. To test this objective, Aim 1 experiments will focus on identifying NB dynamic CEUS kinetics based on NB size and compared to MBs. It will also identify kinetic parameters, margination, and extravasation of NBs in a flow environment in the presence of human whole blood and permeabilized endothelium. These results will help identify the size of extravasated NBs and the degree of endothelial permeability when applied to a more complicated in vivo setup in Aim 2. Aim 2a will use a chick embryo chorioallantoic membrane (CAM) model with controlled levels of permeability to test NB dynamic CEUS parameters in vivo. With known levels of permeability, the CAM results will provide essential information for assessing the extent of permeability in vivo. This method will be applied to an uncontrolled tumor environment in Aim 2b. This proposed research will yield: 1) new information on how contrast agent size affects interaction with red blood cells and dynamic CEUS parameters, 2) a real-time analysis of the tumor-associated EPR effect, yielding new physiological data, and 3) a non-invasive method for determining the extent of pathological permeability in vivo. This proposal will provide crucial knowledge on vascular permeability and extravasation potential of nanoparticles, which is essential to improve patient care.

项目概要在许多慢性炎症性疾病中，血管内皮细胞由于以下原因而变得具有病理渗透性：血管生成以及生长因子和炎症细胞因子（例如组胺、缓激肽等）。在癌症中，这一过程可用于通过增强的纳米粒子递送至肿瘤渗透性和保留（EPR）效应。然而，基于纳米颗粒的治疗方法导致了不一致的结果对患者产生的结果。这是由于多种因素造成的，其中一个主要因素是肿瘤血管结构的异质性无论是在患者之间还是在单个肿瘤内。将纳米颗粒运输至肿瘤并进入实质因免疫系统的摄取、无效的边缘化和低效而变得复杂外渗。需要指导来告知临床医生哪些疗法对每位患者最有效。有效的指导可以降低医疗保健成本和药物的负面副作用。一种廉价、安全、非侵入性实时成像方法可能能够对血管通透性程度进行分类在肿瘤中，一旦得到验证，就可以为患者制定个性化的治疗方案。这样的工具不仅可以用适用于肿瘤，也适用于所有涉及病理性通透性脉管系统的疾病。怀着这个目标，本申请中拟议研究的目标是致力于开发一种实时方法使用新型纳米气泡 (NB) 对比增强技术评估整个肿瘤的血管通透性体内超声（CEUS）。该方法将建立在临床上使用的动态 CEUS 协议的基础上微气泡 (MB)。直径为 100-400 nm 的 NB 已被证明可以外渗到肿瘤中薄壁组织。在开发该方法时使用临床超声将确保最终转化为患者安全、具有成本效益、非侵入性且广泛可及。为了测试这个目标，Aim 1 实验将重点根据 NB 大小并与 MB 进行比较来确定 NB 动态 CEUS 动力学。它还将识别人体存在的流动环境中 NB 的动力学参数、边缘化和外渗血液和通透性内皮。这些结果将有助于确定外渗 NB 的大小和应用于目标 2 中更复杂的体内设置时的内皮通透性程度。目标 2a 将使用具有受控渗透性水平的鸡胚绒毛尿囊膜 (CAM) 模型，用于测试 NB 动态体内 CEUS 参数。在已知渗透率水平的情况下，CAM 结果将提供重要信息用于评估体内渗透性程度。该方法将应用于不受控制的肿瘤环境在目标 2b 中。这项拟议的研究将产生：1）关于造影剂大小如何影响相互作用的新信息具有红细胞和动态 CEUS 参数，2) 实时分析肿瘤相关的 EPR 效果，产生新的生理数据，以及3）一种确定病理程度的非侵入性方法体内渗透性。该提案将提供有关血管通透性和外渗的重要知识纳米粒子的潜力，这对于改善患者护理至关重要。