Photo-hyperpolarized 13C MRI

概括。深层组织（> 1 cm）环境中的高分辨率成像可以解决一系列基础问题 阐明疾病起源和进展机制中的心理和应用问题。虽然荧光- cence 成像是生物分子标记细胞成像的主力技术，但它存在以下问题： 组织深度 >1 毫米处的光散射和像差畸变。在频谱的另一端，mag- 核磁共振成像 (MRI) 是一种成熟且广泛应用的临床前和临床成像技术 该方法对组织深度没有实际限制，但分辨率较低。在这个 在该项目中，我们将创新一类新型超极化 13C 纳米粒子探针，该探针可以作为高效的深 MRI 中的组织标记。我们的中心思想是通过 (i) 光学超波谱显着增强 13C NMR 信号 可以在低磁场下进行激光化，并且 (ii) 13C 相干时间显着延长。 具体来说，我们建议开发基于荧光纳米金刚石（FND）的 MRI 探针，该探针具有 氮空位（NV）中心。与 NV 相关的电子自旋可以在光学上“超极化”并且 极化有效地转移到金刚石 13C 核自旋，从而导致 NMR 信号增强 在临床 MRI 领域，与 13C 热极化相比，其变化超过三个数量级。结合起来，由 实施有效的解耦方案，我们建议显着扩展 13C 自旋相干性，以便能够 对他们进行第二次长时间的审讯。后者产生巨大的信号增益，乘数为 又是 103 倍。结合超极化和自旋相干扩展带来的增益可以实现 信号增益约106 用于 MRI，并将显着提高空间分辨率。而且，由于 偏振是光学产生的，这种 13C 光 MRI (PMRI) 可以在低得多的低场下进行 成本与传统 MRI 基础设施的比较。在我们的方法中，自旋偏振通过光学方式再生，从而允许 重复采集 MRI 数据并进行纵向研究。此外，FND 颗粒本质上是 具有生物相容性，并且其表面适合多种靶向配体。在此基础上，我们提出 开发可进行高保真分辨率成像的靶向荧光纳米粒子 MRI 探针 在深层组织 (>1 cm) 设置中优于 20 um。除了作为明亮的 MRI 试剂外，这些颗粒还具有 明亮的荧光为组织病理学中药物生物分布的交叉检查提供了选择 分析。为了实现这项新技术的前景，我们建议进一步开发超级 larization 和 MR 成像方法，以及通过优化提高纳米颗粒的超极化性 通过合成和加工开发来改变它们的结构。我们的目标是转让 PMRI 技术 我们证明了微米级颗粒到纳米级 FND 适用于体内 MRI。作为其中的一部分 技术演示，我们将在台式（低场）上构建一个简单的原型 PMRI 成像装置 和组织模型中的图像 FND，表征可实现的分辨率和成像深度指标。

Summary. High resolution imaging in deep tissue (> 1 cm) environments can address a swathe of funda- mental and applied problems in the elucidation of mechanisms of disease origin and progression. While fluores- cence imaging is a workhorse technique for the cellular imaging of biological molecular markers, it suffers from light scattering, and aberration distortions at tissue depths >1 mm. On the opposite end of the spectrum, mag- netic resonance imaging (MRI) is a well-established and broadly employed pre-clinical and clinical imaging method that has no practical limitations with respect to tissue depth, but it suffers from low resolution. In this project we will innovate a new class of hyperpolarized 13C nanoparticle probes that can serve as efficient deep tissue markers in MRI. Our central idea is to dramatically boost 13C NMR signal by means of (i) optical hyperpo- larization that can be carried out at low magnetic fields and (ii) significant extension of 13C coherence times. Specifically, we propose to develop MRI probes based on fluorescent nanodiamonds (FNDs) endowed with nitrogen-vacancy (NV) centers. The electronic spins associated with NVs can be optically “hyperpolarized” and that polarization to be effectively transferred to the diamond 13C nuclear spins, resulting in NMR signal enhance- ment over three orders of magnitude vs. 13C thermal polarization at the fields of clinical MRI. In conjunction, by implementing effective decoupling schemes we propose significantly extend the 13C spin coherences to be able to interrogate them for second-long periods. The latter yields enormous signal gains, a multiplicative factor of another 103- fold. Combining the gains due to hyperpolarization and spin coherence extensions permits a total signal gain of ca. 106 for MRI, and will enable a significant improvement in spatial resolution. Moreover, since the polarization is optically generated, this 13C photo-MRI (PMRI), can be carried out at low-field at a much lower cost vs. conventional MRI infrastructure. In our method the spin polarization is regenerated optically, allowing for acquiring MRI data repeatedly and enabling longitudinal studies. Furthermore, the FND particles are inherently biocompatible, and their surfaces are amenable to a versatile set of targeting ligands. With this basis, we propose to develop targetable fluorescent nanoparticle MRI probes that can be imaged with high fidelity with resolution better than 20 um in deep tissue (>1 cm) settings. In addition to being bright MRI agents, the particles are also bright fluorescent providing an option for a cross-examination of the agent biodistribution in histopathological analysis. In order to realize the prospects of this novel technology, we propose to further develop the hyperpo- larization and MR imaging methodologies, as well as boost hyperpolarizability of nanosized particles by optimiz- ing their structure through synthesis and processing developments. We aim at transferring the PMRI technology we demonstrated for micron-sized particles to the nanosized FND suitable for in vivo MRI. As a part of the technology demonstration, we will construct a simple prototype PMRI imaging set-up on the benchtop (low-field) and image FNDs in tissue phantoms, characterizing achievable metrics of resolution and imaging depth.