Gas microbubbles as a hyperpolarized-xenon carrier and as a contrast agent for MRI

气体微泡作为超极化氙载体和 MRI 造影剂

• 批准号: 10196185
• 负责人: Rosa Tamara Branca
• 金额: $ 22.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196185
• 关键词: Antibodies; Automobile Driving; Benchmarking; Biological; Blood; Blood Circulation Time; Blood Vessels; Characteristics; Chemicals; Clinical; Collaborations; Communities; Contrast Media; Coupled; Data; Detection; Diagnosis; Diffusion; Distal; Dose; Drug Delivery Systems; Emulsions; Encapsulated; Environment; FDA approved; Frequencies; Future; Gases; Gene Delivery; Genes; Goals; Human; Image; In Vitro; Inhalation; Kidney; Liquid substance; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Mediating; Microbubbles; Modality; Monitor; Occupations; Organ; Peptides; Perfusion; Pharmaceutical Preparations; Phase; Phospholipids; Physiologic pulse; Predisposition; Production; Property; Protons; Rattus; Relaxation; Research; Research Personnel; Research Project Grants; Role; Safety; Signal Transduction; Solubility; Techniques; Temperature; Testing; Therapeutic; Thermal Ablation Therapy; Time; Tissues; Toxic effect; Translations; Ultrasonography; Water; Xenon; base; biomaterial compatibility; clinical practice; clinical translation; clinically relevant; detection sensitivity; dosage; gadolinium oxide; imaging agent; imaging probe; in vivo; iron oxide; magnetic field; molecular imaging; nanoemulsion; nanovesicle; programs; spectroscopic imaging; targeted delivery

Gas microbubbles have been widely used as ultrasound (US) vascular imaging agents and, more recently, for targeted delivery of drugs and gases in vivo. Their safety profile and their potential as molecular imaging probes make them ideal contrast agents also for MRI. Thus, considering the increase in US/MRI applications that could benefit from a dual-modality contrast agent, gas microbubbles present a promising alternative to gadolinium or iron-oxide based contrast agents. Previous detection of gas microbubbles by MRI has focused primarily on the reduction of the transverse relaxation time (T2 and T2*) of nearby water protons caused by magnetic susceptibility gradients generated at the gas–liquid interface. However, these susceptibility effects are relatively weak. As a result, the microbubble dosage required to obtain acceptable MR contrast is much higher than dosages typically used for clinical ultrasound imaging. We hypothesize that MR sensitivity to gas microbubbles can be enhanced significantly by using HyperCEST. HyperCEST combines Chemical Exchange Saturation Transfer (CEST) and hyperpolarized xenon-129 (HPXe) and can boost MR sensitivity by several orders of magnitude. This hypothesis is supported by recent studies showing hyperCEST detection of gas nanovescicles at picomolar concentrations. Compared to gas nanovescicles, microbubbles have increased xenon-host capacity, lower exchange rate, and a much narrower frequency distribution, thus are expected to saturate hyperCEST detection sensitivity. Additionally, we hypothesize that targeted delivery of gas microbubbles coupled with HPXe inhalation will enhance HPXe signal from distal organs, thereby enabling dissolved-phase xenon MR applications that capitalize on the relatively high solubility of this gas and its impressive sensitivity to its chemical environment. These two hypothesis will be tested through the following specific aims: 1. To characterize and optimize the physical and magnetic resonance properties of microbubbles as hyperCEST agents, in vitro and in vivo; 2. To quantify HPXe signal amplification obtained from US-guided targeted delivery of gas microbubbles. If successful, the proposed research will establish gas microbubbles as a safe and effective dual modality US/MR contrast agent that can easily be disseminated to the research community and transformed into a molecular imaging agent, ultimately resulting in clinical translation. Additionally, direct imaging of gas diffusion in tissues by HPXe after US-assisted targeted release of microbubbles, will enable direct monitoring of microbubbles delivery of biologically active gases and drugs.

燃气微泡已被广泛用作超声（US）血管成像剂，最近 在体内靶向递送药物和气体。他们的安全性和作为分子成像问题的潜力 使其成为MRI的理想对比度。考虑到美国/MRI申请的增加可能 从双模式对比剂中受益，气体微泡是gadolinium或 基于铁氧化物的对比剂。 MRI对气体微泡的先前检测主要集中于横向的还原 附近的水质子的放松时间（T2和T2*）是由磁敏感性梯度引起的 气液界面。但是，这些敏感性效应相对较弱。结果，微泡 获得可接受的MR对比剂所需的剂量远高于通常用于临床的剂量 超声成像。 我们假设通过使用HyperCest可以显着增强对气体微泡的MR敏感性。 HyperCest结合了化学交换饱和转移（CEST）和超极化Xenon-129（HPXE） 并可以通过几个数量级提高MR灵敏度。最近的研究支持了这一假设 在皮摩尔浓度下显示了对气纳维体的超频检测。与气体相比 纳米嵌段，微泡具有提高的氙 - 宿主容量，较低的汇率和较窄的 频率分布，因此有望饱和超频检测灵敏度。 此外，我们假设有针对性的气体微泡和HPXE吸入的量 增强远端器官的HPXE信号，从而实现溶解相氙mr应用 利用这种气体的相对高溶解度及其对化学环境的令人印象深刻的敏感性。 这两个假设将通过以下特定目的进行检验：1。表征和优化 体外和体内微泡的物理和磁共振特性； 2 量化从US引导的气体微泡的靶向输送获得的HPXE信号扩增。如果 成功的研究将确定气体微泡是一种安全有效的双重模式 美国/先生的对比代理，很容易被传播到研究界并转变为 分子成像剂，最终导致临床翻译。此外，直接成像气体扩散 在使用US辅助靶向微泡后，HPXE在组织中，将直接监视 微泡的生物活性气体和药物的递送。