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: 10303690
• 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/10303690
• 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; 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）。尚无临床批准的方法来治疗缺氧后受损的组织 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 动物模型。尽管 Xe 已经得到了更详细的研究，包括早期临床试验，但它可以 极其昂贵且难以获得。 Ar 的价格便宜一百倍并且广泛使用，同时展示 卓越的器官保护效率。此外，Xe 作用的机制取决于它与 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 通过吸入进行全身性治疗，使其对损伤部位没有特异性，可能会降低治疗效果。作为一个 解决方案中，我们建议开发用于局部输送治疗气体的MB（MB）。 MB 是 由于临床超声引起的非线性振荡而具有固有的回声。治疗气体如 然而，由于Ar的水溶性较高，很难在气泡内稳定。团队有 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 壳成分，导致与儿童医院的临床医生进行富有成效的、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 >1010 MB/mL 的高产率配制。优化后的超声信号 ArMB 将在流动模型和小鼠模型中通过测量强度、灌注和 对比度的持久性。 (2)超声介导气泡释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。 ArMB 的有效性将通过增强细胞活力、减少 caspase 来证明 磷脂酰肌醇 3 激酶 (PI3K-AKT) 通路的激活和上调。 （三）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 接触 XeMB。 ArMB 活性即使在谷氨酸受体失活的情况下也会表现出粘合作用 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 IRI 的非侵入性、图像引导治疗，并将其转化为临床环境。