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

2019年诺贝尔生理学或医学奖的颁发证明了对体内氧气可用性研究的多产性。缺氧是由于向活细胞输送的氧气不足而导致身体或身体的一个区域缺氧的情况。它是重要的，因为它是疾病的主要指标。实际上，在各种医学病症中观察到缺氧，例如阿尔茨海默氏病、心血管疾病、肾脏疾病、肝脏和神经障碍、关节炎、代谢疾病、糖尿病、生殖疾病和癌症。在临床医学中，目前还没有检测缺氧的常规方法，但显然，这种技术，基本上作为一种半通用的疾病指标，将在改善医疗保健方面有显着的好处。医学成像是产生身体内部图像的过程，该项目的目的是制造和评估化学化合物，所谓的成像剂，当给予患者时能够对缺氧进行成像。该项目将重点关注含铕的成像剂，因为铕可以形成两种氧化态的稳定化合物，即铕离子上具有不同的电荷，这两种氧化态在生理条件下都是可获得的，并且在与光的相互作用中表现出显着不同的磁性和不同的特性。该项目是基于这样的假设，即在缺氧条件下，Eu 2+状态应该是有利的，而在非缺氧条件下，Eu 3+状态应该是有利的，因此导致生成的图像中的对比度，使得缺氧组织能够被识别。缺氧传感技术的理想特性包括图像中的优异分辨率、非侵入性、无氧消耗、氧浓度的定量测量、和可忽略的毒性。缺氧成像的潜在模式包括磁共振成像（MRI），其是非侵入性的，并且通过使用强磁场和射频脉冲以基本上无限的深度穿透来可视化形态和功能解剖结构。利用MRI将利用铕的氧化态之一产生阳性MRI对比度而氧化态不产生阳性MRI对比度的事实。另一种潜在的缺氧成像方式是光学成像，其也是非侵入性的，并且是基于使用吸收和发射光的分子来可视化亚细胞形态的有力工具。那些既吸收又发射光的材料是所谓的发光材料，并且对于成像特别有用，因为体内表现出发光的化学物质比那些只吸收光的化学物质少，从而导致更清晰的图像。由于铕的一种氧化态比另一种氧化态显示出更长的发光寿命，因此用这种含铕的成像剂进行光学成像也可能产生良好的对比度。本项目将开始合成各种含铕的成像剂，并表征其化学和物理性质及稳定性，随后是体外测试的代理人的MRI和光学成像的缺氧，最后在体内测试这种成像方式。这个项目属于福尔斯的EPSRC物理科学和保健技术的研究领域。

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.