PDF(Pubmed)
Abstract：
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 (KP) 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.
摘要：
造影剂是临床MRI中重要的成像探针,允许识别否则不可能的解剖变化。正在对新型造影剂的开发进行深入研究，以对特定的病理标记物进行成像或感知局部生化变化。最广泛使用的MRI造影剂是基于钆(III)络合物。由于它们非常高的电荷密度，它们通过血脑屏障等紧密的生物屏障具有低渗透性，阻碍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探索了广泛使用的造影剂[Gd（DOTA）]-（Dotarem）与POPC脂质双层之间的相互作用。该金属络合物是标准参考,其中已经引入了几种化学修饰以改善关键性质,例如生物利用度和靶向性。模拟揭示了对代理与脂质双层相互作用的详细见解，提供超越实验方法的观点。各种属性，包括对全球和本地双层属性的影响，进行了分析。不出所料,结果表明该参比化合物具有低分配系数(KP)和高渗透阻隔性。然而，与膜建立有利的相互作用,导致适度长的停留时间。虽然膜相关螯合物保持了一个内球水分子的配位，[Gd(DOTA)]作为MRI造影剂的物理化学属性受到影响。即,观察到内球水的旋转相关时间和停留时间的增加，前者有望显著增加水的质子弛豫率。这项工作建立了一个参考框架，用于使用模拟来指导具有改善的弛豫性和生物利用度的新造影剂的合理设计，以及用于开发用作成像探针或治疗诊断剂的基于脂质体的制剂。
