Interaction of MRI Contrast Agent [Gd(DOTA)]− with Lipid Membranes: A Molecular Dynamics Study

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.

磁共振成像（Magnetic Resonance Imaging, 简称MRI）临床应用中，对比剂是一类关键的成像探针，可实现对常规手段无法观测到的解剖学变化的识别。当前学界正对新型对比剂开展深入研究，以期实现特定病理标志物成像或感知局部生物化学变化。目前临床应用最广泛的MRI对比剂均基于钆(III)配合物。由于此类配合物电荷密度极高，难以透过血脑屏障（blood-brain barrier, BBB）这类紧密的生物屏障，进而限制了其在神经系统疾病诊断中的应用。本研究借助分子动力学模拟手段，探究了临床常用对比剂[钆(DOTA)]⁻（[Gd(DOTA)]⁻，Dotarem）与1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（POPC）脂质双层之间的相互作用。该金属配合物是一类标准参比体系，学界已通过多种化学修饰手段对其进行优化，以改善生物利用度、靶向性等关键性能。本次分子动力学模拟揭示了该对比剂与脂质双层相互作用的微观细节，为研究提供了实验手段难以实现的观测视角。研究团队对多项关键特性展开了分析，包括对比剂对脂质双层整体及局部结构的影响。正如预期，实验结果显示该参比化合物的分配系数（KP）较低，且透过生物屏障的难度较高。尽管如此，该对比剂仍可与脂质双层形成稳定的相互作用，使其在膜表面具备中等偏长的驻留时间。尽管与膜结合的[钆(DOTA)]⁻仍保留了一个内层配位水分子，但其作为MRI对比剂的理化属性仍发生了改变。具体而言，研究观测到其旋转相关时间与内层配位水分子的驻留时间均有所延长，其中旋转相关时间的延长可显著提升水分子质子的弛豫率。本研究为借助模拟手段指导理性设计具备更优弛豫率与生物利用度的新型对比剂，以及开发用于成像探针或诊疗一体化（theranostic）制剂的脂质体制剂提供了参考框架。