Coimbra Chemistry Centre, Institute of Molecular Sciences (CQC-IMS), 3004-535 Coimbra, Portugal.
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Inorg Chem. 2024 Jun 17;63(24):10897-10914. doi: 10.1021/acs.inorgchem.4c00972. Epub 2024 May 25.
Contrast agents are important imaging probes in clinical MRI, allowing the identification of anatomic changes that otherwise would not be possible. Intensive research on the development of new contrast agents is being made to image specific pathological markers or sense local biochemical changes. The most widely used MRI contrast agents are based on gadolinium(III) complexes. Due to their very high charge density, they have low permeability through tight biological barriers such as the blood-brain barrier, hampering their application in the diagnosis of neurological disorders. In this study, we explore the interaction between the widely used contrast agent [Gd(DOTA)] (Dotarem) and POPC lipid bilayers by means of molecular dynamics simulations. This metal complex is a standard reference where several chemical modifications have been introduced to improve key properties such as bioavailability and targeting. The simulations unveil detailed insights into the agent's interaction with the lipid bilayer, offering perspectives beyond experimental methods. Various properties, including the impact on global and local bilayer properties, were analyzed. As expected, the results indicate a low partition coefficient () and high permeation barrier for this reference compound. Nevertheless, favorable interactions are established with the membrane leading to moderately long residence times. While coordination of one inner-sphere water molecule is maintained for the membrane-associated chelate, the physical-chemical attributes of [Gd(DOTA)] as a MRI contrast agent are affected. Namely, increases in the rotational correlation times and in the residence time of the inner-sphere water are observed, with the former expected to significantly increase the water proton relaxivity. This work establishes a reference framework for the use of simulations to guide the rational design of new contrast agents with improved relaxivity and bioavailability and for the development of liposome-based formulations for use as imaging probes or theranostic agents.
对比剂是临床 MRI 中重要的成像探针，可用于识别原本无法识别的解剖结构变化。目前正在进行大量研究，以开发新的对比剂来对特定的病理标志物进行成像或感知局部生化变化。目前应用最广泛的 MRI 对比剂是基于钆（III）配合物的。由于其极高的电荷密度，它们很难穿透紧密的生物屏障，如血脑屏障，这限制了它们在神经疾病诊断中的应用。在这项研究中，我们通过分子动力学模拟研究了广泛使用的对比剂[Gd(DOTA)]（Dotarem）与 POPC 脂质双层之间的相互作用。这种金属配合物是一种标准参考物，已经引入了几种化学修饰，以改善其生物利用度和靶向性等关键特性。模拟揭示了该试剂与脂质双层相互作用的详细信息，提供了超越实验方法的视角。分析了各种特性，包括对全局和局部双层性质的影响。不出所料，结果表明该参考化合物的分配系数（）低，渗透屏障高。然而，与膜之间建立了有利的相互作用，导致停留时间适中延长。虽然与膜相关的螯合物中的一个内球水分子保持配位，但 [Gd(DOTA)] 的物理化学特性作为 MRI 对比剂受到影响。即观察到旋转相关时间和内球水分子停留时间增加，前者预计会显著增加水质子弛豫率。这项工作为使用模拟来指导具有更高弛豫率和生物利用度的新型对比剂的合理设计以及用于成像探针或治疗剂的脂质体制剂的开发建立了参考框架。
