Division of Biology, Chemistry, and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland 20993, USA.
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland 20817, USA.
Toxicol Sci. 2022 Jul 28;188(2):261-275. doi: 10.1093/toxsci/kfac058.
Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have been investigated for biomedical applications, including novel contrast agents, magnetic tracers for tumor imaging, targeted drug delivery vehicles, and magneto-mechanical actuators for hyperthermia and thrombolysis. Despite significant progress, recent clinical reports have raised concerns regarding USPION safety related to endothelial cell dysfunction; however, there is limited information on factors contributing to these clinical responses. The influence of USPION surface chemistry on nanoparticle interactions with proteins may impact endothelial cell function leading to adverse responses. Therefore, the goal of this study was to assess the effects of carboxyl-functionalized USPION (CU) or amine-functionalized USPION (AU) (approximately 30 nm diameter) on biological responses in human coronary artery endothelial cells. Increased protein adsorption was observed for AU compared with CU after exposure to serum proteins. Exposure to CU, but not AU, resulted in a concentration-dependent decrease in cell viability and perinuclear accumulation inside cytoplasmic vesicles. Internalization of CU was correlated with endothelial cell functional changes under non-cytotoxic conditions, as evidenced by a marked decreased expression of endothelial-specific adhesion proteins (eg, vascular endothelial-cadherin and platelet endothelial cell adhesion molecule-1) and increased endothelial permeability. Evaluation of downstream signaling indicated endothelial permeability is associated with actin cytoskeleton remodeling, possibly elicited by intracellular events involving reactive oxygen species, calcium ions, and the nanoparticle cellular uptake pathway. This study demonstrated that USPION surface chemistry significantly impacts protein adsorption and endothelial cell uptake, viability, and barrier function. This information will advance the current toxicological profile of USPION and improve development, safety assessment, and clinical outcomes of USPION-enabled medical products.
超顺磁性氧化铁纳米颗粒（USPION）已被广泛应用于生物医学领域，包括新型对比剂、肿瘤成像的磁性示踪剂、靶向药物输送载体以及用于热疗和溶栓的磁机械致动器。尽管已经取得了显著的进展，但最近的临床报告对 USPION 的安全性提出了担忧，尤其是与内皮细胞功能障碍相关的安全性问题；然而，对于导致这些临床反应的因素，目前的信息还很有限。USPION 表面化学性质对纳米颗粒与蛋白质相互作用的影响可能会影响内皮细胞功能，从而导致不良反应。因此，本研究的目的是评估羧基功能化 USPION（CU）或胺功能化 USPION（AU）（直径约 30nm）对人冠状动脉内皮细胞生物学反应的影响。与 CU 相比，AU 在暴露于血清蛋白后观察到蛋白质吸附增加。暴露于 CU 会导致细胞活力下降，而暴露于 AU 则不会，并且在细胞质囊泡内的核周聚集呈浓度依赖性。在非细胞毒性条件下，CU 的内化与内皮细胞功能变化相关，这表现在内皮特异性粘附蛋白（如血管内皮钙黏蛋白和血小板内皮细胞粘附分子 1）的表达显著降低，以及内皮通透性增加。下游信号转导的评估表明，内皮通透性与肌动蛋白细胞骨架重塑有关，这可能是由涉及活性氧、钙离子和纳米颗粒细胞摄取途径的细胞内事件引起的。本研究表明，USPION 表面化学性质显著影响蛋白质吸附和内皮细胞摄取、活力和屏障功能。这些信息将有助于完善 USPION 的毒理学特性，并改善基于 USPION 的医疗产品的开发、安全性评估和临床结果。
