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

• 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
• 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

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.

项目摘要 在许多慢性炎性疾病中，由于 血管生成和生长因子和炎性细胞因子的生产等疾病（例如组胺， Bradykinin等）。在癌症中，可以利用此过程将纳米颗粒通过增强递送至肿瘤 渗透性和保留效应（EPR）效应。但是，基于纳米颗粒的疗法导致不一致 导致患者。这是由于许多因素，主要因素是异质性肿瘤血管结构 在患者和单个肿瘤内之间。将纳米颗粒传输到肿瘤并进入 通过免疫系统的摄取，无效的边缘和效率低下的实质使实质变得复杂 奢侈。需要指导来告知临床医生哪种疗法对每位患者最有效。 有效的指导可以降低医疗费用和药物的负面影响。便宜，安全， 无创和实时成像方法可能能够分类血管通透性的程度 在肿瘤中，曾经经过验证，对患者的治疗方案个性化。这样的工具不仅可以使用 对于肿瘤，但对于所有涉及病理渗透性脉管系统的疾病。考虑到这个目标， 在本应用程序中拟议的研究的目的是致力于开发一种实时方法 使用新型纳米泡（NB）基于造影剂增强的新肿瘤评估整个肿瘤的血管通透性 超声（CEU）在体内。此方法将基于临床使用的动态CEUS协议 微泡（MB）。 NB的直径为100-400 nm，已显示出外外肿瘤 实质。在开发这种方法中使用临床超声将确保最终翻译为 患者是安全，成本效益，无创的，并且可以广泛访问。要测试这个目标，目标1实验 将专注于基于NB大小并与MBS相比，鉴定NB动态CEU动力学。它也将确定 在人类整体存在下，在流动环境中，NB的动力学参数，边缘和渗出 血液和透化的内皮。这些结果将有助于确定奢侈的NB和 当在AIM 2中应用于更复杂的体内设置时，内皮渗透性程度。AIM2A将使用 雏鸡胚胎绒毛膜膜（CAM）模型具有控制水平的渗透率，以测试NB动态 CEUS参数在体内。具有已知水平的渗透率，CAM结果将提供基本信息 用于评估体内渗透率的程度。该方法将应用于不受控制的肿瘤环境 在AIM 2B中。这项拟议的研究将产生：1）有关对比剂大小如何影响相互作用的新信息 与红细胞和动态CEUS参数有关，2）对肿瘤相关的EPR效应的实时分析， 产生新的生理数据，以及3）一种用于确定病理程度的非侵入性方法 体内渗透性。该建议将提供有关血管渗透性和渗出的重要知识 纳米颗粒的潜力，这对于改善患者护理至关重要。