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.

项目总结