Synthesis and Evaluation of Eu(II/III) Systems for Imaging Transient Hypoxia

从2019年诺贝尔生理学或医学奖的颁奖中可以明显看出对人体氧气可获得性研究的多产性质。缺氧是指由于向活细胞输送的氧气不足而导致身体或身体某一区域缺氧的情况。它之所以意义重大，是因为它是疾病的一个主要指标。事实上，在阿尔茨海默氏症、心血管疾病、肾脏疾病、肝脏和神经疾病、关节炎、代谢性疾病、糖尿病、生殖疾病和癌症等各种医学状况下都会观察到缺氧。在临床医学中，目前还没有常规的方法来检测缺氧，但很明显，这种技术本质上是一种半通用的疾病指示器，将在改善健康方面发挥重大作用。医学成像是生成人体内部图像的过程，该项目的目的是制造和评估化学化合物，即所谓的显像剂，当给患者使用时，这些化合物可以进行缺氧成像。该项目将侧重于含Eu的显像剂，因为Eu可以在两种氧化态下形成稳定的化合物，即在Eu离子上带有不同的电荷，这两种化合物在生理条件下都是可以接触到的，并且在与光的相互作用中显示出非常不同的磁性和不同的性质。这个项目是基于这样的假设，即在低氧条件下Eu2+状态是有利的，在非低氧条件下Eu3+状态是有利的，从而在生成的图像中产生对比度，从而使低氧组织能够被识别。低氧传感技术的理想特性包括图像的良好分辨率、非侵入性、无氧气消耗、氧气浓度的定量测量和可忽略的毒性。低氧成像的潜在模式包括磁共振成像(MRI)，它是一种非侵入性的，通过使用强磁场和射频脉冲显示形态和功能解剖结构，基本上是无限深度穿透。利用磁共振成像将利用这一事实，即Eu的一个氧化态产生正的MRI对比度，而氧化态则不产生。另一种潜在的低氧成像方式是光学成像，它也是非侵入性的，是基于吸收和发射光的分子的使用来可视化亚细胞形态的强大工具。那些既吸收又发光的物质是所谓的发光材料，对成像特别有用，因为人体内发光的化学物质比那些只吸收光的化学物质更少，从而产生更清晰的图像。这种含Eu试剂的光学成像也可能产生良好的对比度，因为Eu的一种氧化态表现出比另一种更长的寿命发光。本项目将从合成各种含Eu的显像剂开始，并表征其化学、物理性质和稳定性，然后是用于磁共振成像和低氧光学成像的试剂的体外测试，最后是此类成像模式的体内测试。该项目属于EPSRC物理科学和医疗技术研究领域。

The prolific nature of research into oxygen availability in the body is evident from the award of the Nobel Prize in Physiology or Medicine 2019. Hypoxia is where the body or a region of the body is oxygen deficient due to insufficient delivery of oxygen to living cells. It is significant because it is a major indicator of disease. Indeed, hypoxia is observed in various medical conditions such as Alzheimer's, cardiovascular diseases, kidney diseases, hepatic and neurological disorders, arthritis, metabolic diseases, diabetes, reproductive diseases, and cancer. In clinical medicine, there are currently no routine methods of detecting hypoxia, but clearly such technology, which essentially acts as a semi- universal indicator of disease, would be of significant benefit in improving healthcare.Medical imaging is the process of generating an image of the interior of the body and the aim of this project is to make and evaluate chemical compounds, so-called imaging agents, that when administered to the patient enable imaging of hypoxia. The project will focus on europium-containing imaging agents because europium can form stable compounds in two oxidation states i.e. with a different charge on the europium ion, which are both accessible under physiological conditions and exhibit dramatically different magnetic properties and different properties in their interaction with light. This project is based on the hypothesis that the Eu2+ state should be favoured under hypoxic conditions, and the Eu3+ state under non-hypoxic conditions, hence leading to contrast in the generated image, enabling hypoxic tissue to be identified.The ideal properties for a hypoxia sensing technique encompass excellent resolution in the image, non- invasiveness, no oxygen consumption, quantitative measurement of oxygen concentration, and negligible toxicity. Potential modes of imaging hypoxia include Magnetic Resonance Imaging (MRI) which is non-invasive and visualises morphological and functional anatomy with essentially unlimited depth penetration through use of strong magnetic fields and radiofrequency pulses. Utilising MRI would exploit the fact that one of the oxidation states of europium produces positive MRI contrast whereas the oxidation state does not. Another potential hypoxia imaging modality is optical imaging which is also non-invasive and is a powerful tool for visualising subcellular morphologies based on the use of molecules that absorb and emit light. Those that both absorb and emit light are so-called luminescent materials and are particularly useful for imaging as there are fewer chemical species in the body that exhibit luminescence than those that just absorb light, leading to a more defined image. Optical imaging with such europium-containing agents is also likely to produce good contrast because one of the oxidation states of europium displays longer lived luminescence than the other.This project will begin with synthesis of various europium-containing imaging agents and characterisation of their chemical and physical properties and stability, followed by in vitro testing of the agents for MRI and optical imaging of hypoxia and finally in vivo testing of such imaging modalities.This project falls within the EPSRC physical sciences and healthcare technologies research areas.