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、图像引导、局部治疗使用回声氩微泡对神经元和心脏模型中的缺血再灌注损伤 (IRI) 进行研究（ArMB）尚无临床批准的治疗缺氧后受损组织的方法。缺血性和再灌注损伤，例如中风或心脏骤停惰性气体，如氩 (Ar) 和氙 (Xe)。是非常有前途的细胞保护剂，已被证明可以在体外和体内成功治疗急性 IRI 然而，Xe 已经得到了更详细的研究，包括在早期临床试验中，它可以 Ar 的价格昂贵且难以获得，但价格却便宜一百倍，而且在展出的同时也很容易获得。优异的有机保护效率此外，Xe 的作用机制取决于其与据报道，Ar 通过刺激细胞膜上的谷氨酸受体来发挥作用细胞保护信号通路，使其成为更通用的抗凋亡剂。目前的Ar治疗时间较长。和全身性的，通过吸入，使其对损伤部位不具有特异性，可能会降低治疗效果。解决方案，我们建议开发用于治疗气体局部输送的MB（MB）。由于临床超声等治疗气体引起的非线性振荡，因此具有固有的回声。然而，由于Ar的水溶性较高，很难在气泡内稳定。最近通过优化，成功地小规模生产了稳定、回声、惰性气体MB MB 外壳组合物，导致与儿童医院的新人进行富有成效的、持续的合作费城（CHOP）。拟议的研究将通过实施三个具体项目来进行。目标 (1) 1-10 µm ArMB 将以每毫升 >1010 MB 的高产量配制。 ArMB 将在流动模型和小鼠模型中通过测量强度、灌注和 (2)超声介导的气泡释放Ar治疗IRI的疗效。将在基于体外细胞培养的氧诱导神经元和心脏损伤模拟中进行估计葡萄糖剥夺的有效性将通过细胞活力的增强、半胱天冬酶的减少来证明。磷脂酰肌醇 3 激酶 (PI3K-AKT) 通路的激活和上调 (3) 进一步激励。使用 ArMB 将通过将 IRI 处理结果与细胞大量 Ar 暴露的结果进行比较来识别即使谷氨酸受体失活，暴露于 XeMB 也会发挥作用。 ArMB 用于各种细胞保护治疗的可行性 PI 团队将利用他们在这方面的专业知识。胶体设计、细胞动力学和超声成像精确设计 ArMB 外壳并严格确定这种新型廉价药物在体外的有效性，以实现团队测试 ArMB 的长期目标在大型动物模型中进行非侵入性、图像引导的 IRI 治疗，并将其转化为临床环境。