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

基本信息

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
项目类别：
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

项目摘要

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.

该提案的关键健康意义涉及超声介导的图像引导，局部治疗使用Echogenic Argogenic Argon Microbubbles在神经元和心脏模型中的缺血再灌注损伤（IRI）（臂）。经历低氧后，没有临床批准的方法来治疗受损坏的组织缺血性和再灌注损伤，例如中风或心脏骤停。昂贵的气体（AR）和氙气（XE）是高度有希望的细胞保护剂，已证明可以在体外和IN成功处理急性IRI 动物模型。 XE对XE进行了更详细的研究，包括在早期临床试验中，但可以是过于昂贵且难以获得。 AR在展示时便宜一百倍，可广泛可用出色的有机保护效率。此外，XE动作的机制取决于其与细胞膜上的谷氨酸受体，据报道AR通过刺激各种内源性而起作用细胞保护信号通路，使其成为更通用的抗凋亡剂。当前的AR疗法很长系统性通过吸入，使其对损伤部位的特异性非特异性，可能会减少治疗作用。作为解决方案，我们建议开发MBS（MB），以局部递送治疗气体。 MB是由于其非线性振荡是由临床超声引起的。这样的治疗气体然而，由于AR由于前者的高水溶性而难以稳定在气泡内部。团队有最近，通过优化了稳定的，回声，高贵的气体MB的小型生产，通过优化 MB壳的组成，导致与儿童医院的临床医生进行富有成效的合作费城（Chop）。拟议的研究将通过实施三个特定目标。（1）1-10 µm臂将以每毫升> 1010 MB的高收率配制。优化的超声信号通过测量大小，灌注和对比的持久性。（2）超声介导的AR从气泡中释放的治疗作用在处理IRI中将在基于体外细胞培养的神经元和心脏损伤的模拟中估计葡萄糖剥夺。 ARMB的有效性将通过增强的细胞活力证明，caspase的降低磷脂酰肌醇3激酶（PI3K-AKT）途径的激活和上调。（3）进一步的激励将使用ARMB的IRI治疗结果与大量AR暴露于细胞和细胞的结果进行识别暴露于Xembs。即使在谷氨酸受体停用的情况下，ARMB活性也会显示为水泥 ARMB对各种细胞保护治疗的可行性。 PI团队将利用他们的专业知识胶体设计，蜂窝动力学和超声成像，以精确地设计臂章和严格在体外确定这个新的，廉价的代理商的有效性，以实现该团队测试ARMB的长期目标在大型动物模型中对IRI的无创，图像引导的处理，并将其转化为临床环境。