Ultrasound image-guided treatment of ischemia-reperfusion injury using argon microbubbles

超声图像引导氩气微泡治疗缺血再灌注损伤

• 批准号: 10415201
• 负责人: Daeyeon Lee
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415201
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Dimensional; Acoustics; Acute; Animal Model; Animals; Applications Grants; Argon; Biological Assay; Biological Markers; Blood Circulation; CASP3 gene; Cardiac; Caspase; Cell Culture Techniques; Cell Line; Cell Survival; Cell membrane; Cells; Centrifugation; Clinic; Clinical; Collaborations; Colloids; Cytoprotective Agent; Development; Encapsulated; Engineering; Ensure; Environment; Exhibits; Exposure to; Formulation; Future; Gases; Glucose; Glutamate Receptor; Goals; Health; Heart Arrest; Heart Injuries; Hypoxia; In Vitro; Incentives; Inhalation; Injury; Kidney; Length; Lipids; Liposomes; Literature; Measures; Mediating; Methods; Microbubbles; Microfluidics; Modeling; Myocardial Infarction; Neuronal Injury; Neurons; Nitric Oxide; Noble Gases; Oxidative Stress; Oxygen; Pathway interactions; Pediatric Hospitals; Perfusion; Philadelphia; Phospholipids; Physiological; Preclinical Testing; Preparation; Production; Property; Proto-Oncogene Proteins c-akt; Protocols documentation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Rest; Signal Pathway; Signal Transduction; Site; Solubility; Sonication; Stroke; System; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Translations; Traumatic Brain Injury; Ultrasonography; Up-Regulation; Validation; Work; Xenon; aqueous; base; clinical application; deprivation; design; disability; early phase clinical trial; efficacy evaluation; efficacy testing; experience; hypoxic ischemic injury; image guided; image guided therapy; improved; in vivo; in vivo imaging; interfacial; ischemic injury; mouse model; non-invasive imaging; prevent; scale up; side effect; simulation; theranostics; treatment effect; ultrasound; validation studies

The key health significance of this proposal involves the ultrasound-mediated, image-guided, localized treatment of ischemia reperfusion injury (IRI) in neuronal and cardiac models using echogenic argon microbubbles (ArMBs). There exist no clinically approved methods for treating damaged tissue after experiencing hypoxic ischemic and reperfusion injuries such as stroke or cardiac arrest. Noble gases like argon (Ar) and xenon (Xe) are highly promising cytoprotective agents that have been shown to successfully treat acute IRI in vitro and in animal models. Whereas Xe has been researched in greater detail including in early clinical trials, it can be prohibitively expensive and difficult to obtain. Ar is a hundred times cheaper and widely available, while exhibiting excellent organoprotective efficiency. Furthermore, the mechanism of Xe action depends on its interaction with glutamate receptors on cell membranes, whereas Ar is reported to work by stimulating various endogenous cellular protecting signaling pathways, making it a more versatile antiapoptotic agent. Current Ar therapy is long and systemic, via inhalation, making it non-specific to the injury site, likely diminishing therapeutic effect. As a solution, we propose the development of MBs (MBs) for localized delivery of the therapeutic gas. MBs are inherently echogenic due to their non-linear oscillations induced by clinical ultrasound. Therapeutic gases such as Ar, however, are difficult to stabilize inside bubbles due to the former's high aqueous solubility. The team has recently succeeded in small-scale production of stable, echogenic, noble gas MBs through optimization of the MB shell composition, leading to a productive, ongoing collaboration with clinicians at the Children's Hospital of Philadelphia (CHOP). The proposed research will be conducted through the implementation of three specific aims. (1) 1-10 µm ArMBs will be formulated at a high yield of >1010 MBs per mL. Ultrasound signal of optimized ArMBs will be investigated in flow phantoms and in a mouse model by measuring the magnitude, perfusion, and persistence of contrast. (2) The therapeutic effect of ultrasound mediated Ar release from bubbles in treating IRI will be estimated in in vitro cell culture-based simulations of neuronal and cardiac injuries induced by oxygen glucose deprivation. The validity of ArMBs will be proved by enhanced cell viability, decrease in caspase activation, and upregulation in the phosphatidylinositol 3 kinase (PI3K-AKT) pathway. (3) Further incentive to use ArMBs will be recognized by comparing their IRI treatment results to that of bulk Ar exposure to cells and exposure to XeMBs. ArMB activity even with the deactivation of glutamate receptors will be shown to cement the feasibility of ArMBs for a variety of cytoprotective treatments. The PI team will leverage their expertise in colloidal design, cellular dynamics, and ultrasound imaging to precisely engineer the ArMB shell and to rigorously establish the validity of this new, inexpensive agent in vitro for the team's long-term goal of testing ArMBs for non-invasive, image guided treatment of IRI in large animal models and translating them to clinical settings.

该建议的关键健康意义涉及超声介导，图像引导，局部治疗