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

气体微泡已被广泛用作超声（US）血管成像剂，并且最近， 体内药物和气体的靶向递送。它们的安全性和作为分子成像探针的潜力 使其成为MRI的理想造影剂。因此，考虑到US/MRI应用的增加， 受益于双模态造影剂，气体微泡是钆或 氧化铁基造影剂。 先前通过MRI检测气体微泡主要集中在横突的减少上。 附近的水质子的弛豫时间（T2和T2*）由磁化率梯度产生， 气液界面然而，这些磁化率效应相对较弱。结果，微泡 获得可接受的MR对比度所需的剂量远高于通常用于临床的剂量。 超声成像 我们假设使用HyperCEST可以显著增强MR对气体微泡的敏感性。 HyperCEST结合了化学交换饱和转移（CEST）和超极化氙-129（HP 129） 并且可以将MR灵敏度提高几个数量级。这一假设得到了最近研究的支持 显示了在皮摩尔浓度下的气体纳米囊泡的高CEST检测。与天然气相比 纳米囊泡、微泡具有增加的氙宿主容量、较低的交换速率和窄得多的 频率分布，因此预期使hyperCEST检测灵敏度饱和。 此外，我们假设，靶向递送气体微泡与HPV 16吸入结合， 增强来自远端器官的HPVs信号，从而实现溶解相氙MR应用， 利用这种气体相对较高的溶解度及其对化学环境的敏感性。 这两个假设将通过以下具体目标进行检验：1.为了表征和优化 作为hyperCEST试剂的微泡在体外和体内的物理和磁共振性质; 2.到 量化从US引导的气体微泡的靶向递送获得的HPV 16信号放大。如果 成功的，拟议的研究将建立气体微泡作为一个安全和有效的双重模式 US/MR造影剂，可以很容易地传播到研究界，并转化为 分子成像剂，最终导致临床转化。此外，气体扩散的直接成像 在超声辅助靶向释放微泡后，通过HPVs在组织中的应用，将能够直接监测 微泡递送生物活性气体和药物。

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.