Center for X-ray Analytics, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen 9014, Switzerland; Particles-Biology Interactions Laboratory, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014 St. Gallen, Switzerland; Department of Chemistry, University of Fribourg, Chemin du Musée 9, 1700 Fribourg, Switzerland.
Center for X-ray Analytics, Empa, Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, St. Gallen 9014, Switzerland.
J Control Release. 2024 Apr;368:566-579. doi: 10.1016/j.jconrel.2024.02.044. Epub 2024 Mar 14.
Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes. We therefore investigated the core-ligand structure of two clinically relevant iron-carbohydrate complexes, iron sucrose (IS) and ferric carboxymaltose (FCM), and their interactions with two structurally different human plasma proteins, human serum albumin (HSA) and fibrinogen, using a combination of cryo-scanning transmission electron microscopy (cryo-STEM), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS). Using this orthogonal approach, we defined the nano-structure, individual building blocks and surface morphology for IS and FCM. Importantly, we revealed significant differences in the surface morphology of the iron-carbohydrate complexes. FCM shows a localised carbohydrate shell around its core, in contrast to IS, which is characterised by a diffuse and dynamic layer of carbohydrate ligand surrounding its core. We hypothesised that such differences in carbohydrate morphology determine the interaction between iron-carbohydrate complexes and proteins and therefore investigated the NPs in the presence of HSA and fibrinogen. Intriguingly, IS showed significant interaction with HSA and fibrinogen, forming NP-protein clusters, while FCM only showed significant interaction with fibrinogen. We postulate that these differences could influence bio-response of the two formulations and their clinical outcome. In conclusion, our study provides orthogonal characterisation of two clinically relevant iron-carbohydrate complexes and first hints at their interaction behaviour with proteins in the human bloodstream, setting a prerequisite towards complete understanding of the correlation between physicochemical properties and clinical outcome.
静脉内（IV）铁碳水化合物复合物被广泛用作治疗缺铁性贫血的纳米颗粒（NPs），常用于治疗慢性肾病、心力衰竭和各种炎症等疾病。尽管这些产品有大量的物理化学特性和临床研究数据，但铁碳水化合物复合物的物理化学特性与临床结果之间的循证相关性尚未完全阐明。对其他金属氧化物 NPs 的研究表明，IV 注射后 NPs 与血液的早期相互作用是理解铁碳水化合物复合物的物理化学特性差异如何导致临床结果差异的关键。因此，我们使用冷冻扫描透射电子显微镜（cryo-STEM）、X 射线衍射（XRD）、小角 X 射线散射（SAXS）和小角中子散射（SANS）相结合的方法，研究了两种临床相关的铁碳水化合物复合物（蔗糖铁[IS]和羧麦芽糖铁[FCM]）及其与两种结构不同的人血浆蛋白（人血清白蛋白[HSA]和纤维蛋白原）的相互作用。通过这种正交方法，我们确定了 IS 和 FCM 的纳米结构、单体和表面形态。重要的是，我们揭示了铁碳水化合物复合物表面形态的显著差异。FCM 在其核心周围显示出局部碳水化合物壳，而 IS 则以其核心周围扩散和动态的碳水化合物配体层为特征。我们假设这种碳水化合物形态的差异决定了铁碳水化合物复合物与蛋白质的相互作用，因此研究了 NP 在 HSA 和纤维蛋白原存在下的相互作用。有趣的是，IS 与 HSA 和纤维蛋白原表现出明显的相互作用，形成 NP-蛋白簇，而 FCM 仅与纤维蛋白原表现出明显的相互作用。我们推测这些差异可能会影响两种配方的生物反应及其临床结果。总之，我们的研究提供了两种临床相关的铁碳水化合物复合物的正交表征，并首次暗示了它们与人类血液中蛋白质的相互作用行为，为全面理解物理化学特性与临床结果之间的相关性奠定了基础。
